Method of preparing a dosage unit by direct tableting and product therefrom

ABSTRACT

The present invention is a process and apparatus for making a dosage unit by direct tableting of shearlite particles. The present invention also includes the dosage unit itself. Shearlite particles, which are prepared by subjecting a feedstock material to liquiflash processing, can be directly fed from a shearlite device to a tableting apparatus without the necessity of any intermediate steps or additional ingredients to facilitate flowability or tablet formation.

This application is a continuation-in-part application of U.S.application Ser. No. 08/330,412 filed Oct. 28, 1994 now U.S. Pat. No.5,683,720.

BACKGROUND OF THE INVENTION

The present invention relates to the preparation of dosage units fordelivering bio-affecting agents, e.g., compressed tablets, and, inparticular, relates to improved methods of manufacturing such units, aswell as improved ingredients therefor.

Compressed tablets are prepared by compressing a formulation containinga medicinal substance or drug and other ingredients, such as excipientsselected for properties which enhance the production and use of thetablet. There are currently three known basic methods for preparingtablet granulations. These are wet granulation, dry granulation anddirect compression. Both wet and dry granulations involve the formationof an agglomerate for feeding to a die cavity. Direct compressionusually involves compressing a powder blend of an active ingredient withsuitable excipients.

The preparation of formulations for tableting by wet granulation is theoldest method and still the most widely used. Wet granulation involvesmany steps, including: milling of drugs and excipients, mixing of themilled powders, preparation of binder solution, mixing of the milledpowders, preparation of binder solution, mixing of binder solution withpowder mixture to form a wet mass, coarse screening of the wet massusing 6-12 mesh screens, drying of moist granules, screening of drygranules with lubricant and disintegrant, and tablet compression.

Wet granulation is an expensive process because it requires manyprocessing steps and involves considerable material handling equipment.Consequently, the process requires both energy and substantial spacewhich should be environmentally controlled.

Dry granulation refers to the granulation of a powder mixture bycompression without the use of heat and solvent. Dry granulation is usedwhen wet granulation is not available because the drug is sensitive tomoisture or heat.

Two methods are used for dry granulation. One method is slugging, wherethe powder is precompressed on a heavy-duty tablet press, and theresulting tablets or slugs are milled to yield the granulation. Theother method is precompression of the powder with pressure rolls using acompactor.

Dry granulation has many disadvantages. It requires a specializedheavy-duty tablet press to form the slug; it does not permit uniformcolor distribution as can be achieved with wet granulation, where dyecan be incorporated into the binder liquid; the pressure roll presscannot be used with insoluble drugs because this may retard thedissolution rate; and the process tends to create dust therebyincreasing the potential for cross-contamination.

Direct compression tableting has the least amount of steps. Directcompression is used in a process by which tablets are compresseddirectly from powder blends of the active ingredient and suitableexcipients (including fillers, disintegrants, and lubricants) which areincluded in the mix to provide uniform flow into the die cavity and forma firm solid compression tablet. No pretreatment of the powder blends bywet or dry granulation procedures is necessary.

Although it has considerably fewer steps than either wet or drygranulation processes, direct compression also has many technologicallimitations. These limitations include primarily obtaining sufficientflow, and obtaining bonding of particles to form a strong compressedtablet. Low-dose drugs are difficult to blend, that is, uniformdistribution of the drug is not easily attained and unblending sometimesoccurs during the compression stage. High-dose drugs do not lendthemselves to direct compression because of poor flowability and poorcompressibility. A typical example would be some of the antacid drugs,such as aluminum hydroxide and magnesium carbonate.

When direct compression is used the choice of excipients is extremelycritical. It is desirable that when using direct compression fillers andbinders possess both compressibility and fluidity. In addition tocompressibility failures, the process of direct compression also hasdisadvantages in the area of blending. Direct compression blends aresubject to unblending in post blending handling steps. Differences inparticle size because of differences in density between drug andexcipient particles may also lead to unblending in the hopper orfeedframe on the tablet press.

A disadvantage of all prior art process is the production of finesusually associated with making compression tablets. In the prior art,preparation of particles for formulation of tablets by compressionresults in a noticeable amount of fines, i.e., very tiny particles onthe order of 150 microns and less. Fines interfere with operation ofapparatus for feeding tableting machines as well as the operation of thetableting machines. Often, it is necessary to conduct tablet productionin a facility which is environmentally controlled to eliminate or reducethe fines. This adds to the cost of production of the tablets.

Moreover, a percentage of the non-compressed particulate is lost duringproduction because there are fines dispersed and cannot be recaptured,and because some of the fines are not capable of being recovered forrecycle.

It is desirable to provide a method for direct compression tabletmanufacturing which includes advantages of wet and dry granulation andtraditional direct compression but does not have the disadvantagesassociated therewith.

In commonly owned U.S. Pat. No. 4,855,326 to Fuisz, the inventor haspreviously disclosed that a fiber form of medicament-bearing product canbe compacted to form a sheet-like body. He cautions, however, that thecompact body cannot be squeezed too much for fear of breaking thefibrous mass. There is no indication to form a compressed tablet as amedicinal dosage form.

Similarly, in U.S. Pat. No. 4,873,085 a spun fibrous cosmetic isdisclosed as well as a compacted form of sugar fibers to form asheet-like body which can be handled more readily. There is noindication to form a compressed tablet.

In U.S. Pat. No. 4,997,856, a wafer-like structure is disclosed in whicha medicament is distributed on or through spun fibers which are thenchopped by passing through a conventional "food grinder" (Hobarthamburger grinder). The enclosed volume of the end product is less than30%, and preferably less than 15%, of the as-spun volume of floss. Thereis no mention in the '856 disclosure to form a compressed tablet.

The use of compacted spun fibers in the same sense as in the patentsmentioned above is also disclosed in U.S. Pat. No. 5,034,421 and U.S.Pat. No. 5,096,492. None of these disclosures suggest formation of acompressed tablet.

Commonly-owned, copending U.S. application Ser. No. 08/194,682 filedFeb. 10, 1994 discloses a method for making edible units and producttherefrom made by compressing shearform matrix masses sufficiently toform a comestible compression unit. Commonly-owned copending U.S.application Ser. No. 08/259,258 filed Jun. 14, 1994 discloses a methodfor preparing a quick-dissolve comestible unit by initiatingcrystallization of shearform matrix and combining with an additive,either before or after initiating crystallization, to form flowable,compactible micro-particulates and then subjecting the resultmicro-particulates to compacting, and the product therefrom.Commonly-owned copending U.S. application Ser. No. 08/259,496 filed Jun.14, 1994 discloses a method of preparing a rapidly dissolving comestibleunit by mixing uncured shearform matrix and an additive, molding a unitdosage form, and curing the matrix in the molded condition, and theproduct therefrom.

The above-identified parent application, which is incorporated herein byreference, describes a method for preparing discrete particles and theproduct resulting from the inventive method. Particles resulting fromthis method have highly consistent size and shape, which issubstantially spheroidal. Thus, the disclosed method is highly efficientand predictable.

As a result of the consistent size and substantially spheroidal shape,the product has been found to have excellent flow properties. The flowproperty of a substance as used herein means the ability of thesubstance to flow. A mass of material can be made to flow by tilting thesurface on which a quantity of the material results until it moves underthe force of gravity in a direction away from the "at rest" position. Asubstance with good flow properties will move easily and evenly awayfrom the "at rest" position. Such a material is easily utilized inprocessing apparatus for preparing compressed tablets, capsules, etc.Substances without good flow properties, do not readily flow, andgenerally do not move in an even condition. Such substances generallyare transported in the form of clumps or uneven masses from the "atrest" position.

It is believed the unique properties of the product set forth in theparent application can be used to improve dosage units prepared bytraditional tableting methods.

The present invention is, therefore, intended to overcome theshortcomings found in traditional tablet-making procedures, and toprovide a significantly improved method of making tablets. These andother objects of the present invention will be realized by those skilledin the art in view of the following disclosure.

SUMMARY OF THE INVENTION

The present invention is a process for making a dosage unit fordelivering a bio-affecting agent and a product resulting from theprocess. The process includes directly tableting shearlite particles.Shearlite particles are defined herein as discrete particles which areprepared by subjecting a solid organic-based feedstock to liquiflash andshearing conditions. The shearlite particles can be made from an activeingredient, a combination of active ingredients, a non-activeingredient, or a combination of active and non-active ingredients. Infact, it has been found that shearlite particles of non-activeingredients can be beneficially used as excipients in the process ofmaking some of the dosage units of the present invention. "Directlytableting" as used herein means to compress shearlite particles,subsequent to their formation, without any intermediate processing stepsor additional ingredients, if so desired. Thus, "directly" is a termidentifying the elimination of steps and/or ingredients normallyconsidered essential in traditional tablet making procedures. Withreference to wet granulation and dry granulation procedures, the presentinvention has eliminated many interim steps and ingredients used toobtain the proper size of particles and adequate flowability to enabletransport to and through tableting apparatus. The present invention hasalso removed the requirement for many excipients (e.g., fillers,disintegrants and lubricants), previously considered necessary even intraditional direct compression methods. However, as previouslydescribed, excipients in the form of shearlite particles can bebeneficially utilized in accordance with the present invention.

Preferably the feedstock used to prepare shearlite particles is a solidorganic-based feedstock, capable of being transformed to a liquiform inthe substantial absence of a dissolving medium. The feedstock, thusreduced to unimpeded internal flow under liquiflash conditions, issubsequently discretized by natural mass separation of the flowingfeedstock in the presence of shear force to form shearlite particles.

"Liquiflash conditions" as used herein means those conditions whichprovide transformation of a solid to a liquid state and then to thesolid state (e.g., solid-liquid-solid) instantaneously. Byinstantaneously is meant less than seconds, in most cases on the orderof fractions of a second, most preferably milli-seconds. Thus, certainlythe transformation from solid to liquid to solid takes place in a timeperiod of less than five seconds, preferably less than one second, andmost preferably less than 0.1 seconds.

During this rapid transition, shear forces can act on the material todiscretize the feedstock. Thus, liquiflash conditions are thecombination of temperature and force which induce an organic-basedfeedstock to flow and re-solidify into a changed shape as it is beingdiscretized by the action of shear force. In preferred embodiments thesize and the new shape are highly consistent among the discretizedparticles. Thus, the shape is preferably spheroidal and the sizedistribution is very limited with only minor variations.

The highly consistent spheroidal shape and the narrow range of sizedistribution causes the shearlite particles to flow evenly and easily.The discrete shearlite particles produced are preferably microspheres,which as used herein preferably means not greater than about 500 μm,more preferably not greater than about 400 μm, and most preferably notgreater than about 300 μm. In the preferred method of the presentinvention the liquiflash conditions are provided by a spinning headhaving a heated peripheral barrier with exit openings providedtherethrough for passage of feedstock flowing under centrifugal force.The shear force referred to above is imparted to flowing feedstock byresistance of air pressure against the liquiform feedstock as it exitsthe spinning head.

The ambient atmosphere can be undisturbed except by the motion of thespinning head. Alternatively, the ambient atmosphere about the spinninghead can be a positive counter or concurrent flow adjacent the outsidesurface of the processing barrier. This permits greater control ofseparation of the liquiform feedstock.

The discrete particles separated from the mass of flowing feedstock arecooled. In a preferred form of the present invention the discreteparticles are monodispersed. "Monodispersed" as used herein refers tothe production of a plurality of uniform spherical particulates, e.g.,shearlites. As explained hereinabove methods for barrier processing offeedstock known in the art generally results in a product having a widevariety of sizes and shapes. This is due to many factors all of whichcontribute to a basic lack of control over the formation ofparticulates.

In the present invention, however, natural mass forming forces availablein minute material masses, e.g., entropy, et al., provide a predictableuniform size. Thus, monodispersed means that at least about 40% byweight, preferably at least about 60% by weight and most preferably atleast about 80% of the product herein have a largest diameter which iswithin 60% of the mean particle diameter. Particle diameter is thedimension which is the greatest straight line dimension in the largestplane taken through a three dimensional particulate. Generally, when theparticulate is spheroidal in shape, the particulate diameter is thediameter of the spheroid. In a preferred embodiment, monodispersabilitymeans that at least 40% of the particulates are within 50% of the meanparticulate diameter, and, in a most preferred embodiment, within 40% ofthe mean particulate diameter.

Processable feedstock materials used in the present invention arepredominantly "organic material." Organic material as used herein meanscarbon containing compounds, e.g., composition and structure of carboncontaining compounds, whereas inorganic materials (or compounds) pertainto substances which do not contain organic type carbon. Polycarboncarbon compounds are preferably used in the present invention.Hydrocarbons are a major portion of organic materials, and are alsopreferred for use herein. Metals, inorganic carbonates and silicates,e.g., glass, are not considered organic materials for purposes of thepresent invention. Furthermore, proteinaceous material having highmolecular weight is not considered "organic material" as used herein.

In a preferred embodiment of the present invention, the feedstockmaterial includes a medicament so that the resulting product can be adelivery system for inclusion in a dosage unit.

Another preferred embodiment is a sucrose product having a highlyconsistent small size and spheroidal shape. The size range is from 5 μmto 100 μm, and is preferably from 10 μm to 50 μm--ideally 15 μ-30 μ,centered around 25 μm.

In one preferred embodiment the shearlite discrete particles consist ofa medicament which has a solid spherical body having substantially nodiscontinuity therein. Consequently, the spherical body can be asubstantially pure drug or active ingredient which is at least 80% ofthe theoretical density of the drug at standard temperature andpressure, and is preferably at least 90%, and most preferably not lessthan 95% theoretical density.

Preferably, the spherical body or bodies are shearlite microspheres asdefined herein. As a result of the present invention drugs orcombinations of drugs can be combined with excipients and prepared on acommercial scale to provide spherical particles having a high degree ofsize consistency. This capability provides a major advantage in the artof preparing controlled released delivery systems.

The product of the present invention can be a true amalgam of differentdrugs or active components or combinations of amalgams and mixtures ofdrug and non-drug ingredients, including ingredients previously believedincompatible, interactive or unstable, e.g., vitamin B₁₂ and minerals.If two or more drug components included in the feedstock have similarmelting points, the product will usually be a true amalgam of the drugcomponents. If one or more of the active ingredients has a highermelting point than one or more of the other components, the highermelting drug will disperse substantially and consistently throughout theliquiform when the lower melting point ingredients are processed.Finally, one of the components, such as the low melting pointingredient, can be a non-active ingredient. For example, sucrose can beused in combination with active ingredients to form a sphericalparticulate product having an active ingredient substantially and evenlydistributed throughout. One particularly useful combination of activeagents includes agents used as cough and cold treatment.

In preferred embodiments of this aspect of the invention, the feedstockcan be a saccharide based material, preferably, a sugar. Alternatively,the feedstock material can itself be a medicament which includes one ormore active agents.

The medicaments contemplated for use in this aspect of the inventioninclude one or more active agents as set forth hereinbelow.Controlled-release substances are those which are known in the art, someof which have been set forth with specificity in the present disclosure.Taste-altering substances include taste-masking substances, sweeteners,flavorings, and, in general, any substance which changes the naturalorganoleptic perception of the product resulting from the liquiflashprocessing.

In a further preferred embodiment of the present invention, themedicament includes an anti-inflammatory substance which is anon-steroidal anti-inflammatory agent selected from the group consistingof salicylates, acetic acids, propionic acids, fenamates, oxicams, andtenidap. A particularly preferred non-steroidal anti-inflammatory agentis ibuprofen which is a propionic acid anti-inflammatory agent. Otherpropionic acid anti-inflammatory agents includes flurbiprofen, naproxen,and ketoprofen.

In yet another preferred embodiment of the present invention, themedicament includes H₂ -antagonists as an active agent.

In another embodiment of the present invention, the dosage units caninclude, in addition to the shearlite particles of medicament describedabove, shearlite particles of non-active ingredients as excipients.Preferably, the excipient shearlite particles are formed from afeedstock of a saccharide based material that has been subjected toliquiflash conditions. Examples of saccharide based materials includesugars such as sucrose, sugar alcohols such as mannitol, and mixturesthereof.

Alternatively, dosage units of the present invention can be formed fromthe shearlite particles of medicament mentioned above and an excipientmaterial in a non-shearlite condition, e.g., a floss or powder.

Another aspect of the present invention is an apparatus for makingdosage unit which includes a shearlite particle making device("shearlite device") connected for direct feed of shearlite particles toa tablet-making machine. The shearlite device is one such as thatdescribed in the parent application, and tablet-making machine similarto those known in the art can be used in the present invention. Directfeed from the shearlite device to the tablet-making machine can be aparticulate conveyor (e.g., conduit, tray, track, etc.) which is used totransfer shearlite particles and is used herein to identify the lack ofrequired assisting mechanisms.

As a result of the present invention, substances which are known torequire multiple preparation steps and/or additional ingredients toprepare a tablet, can now be tableted without such steps and/oringredients.

For example, ascorbic acid, which was previously considered tabletableonly after preparation with additional steps and ingredients, can now bedirectly tableted in the sense of the present invention.

Another advantage of the present invention is that excipients can beprovided having a particle size and shape thoroughly compatible with theactive-containing shearlite particles. This condition, in turn, providescomplete physical homogeneity and enhances machine handling of thetableting formulation. More specifically, it has been found that theexcellent flowability of the tableting formulation to the tabletingapparatus is maintained while utilizing non-active shearlite particlesas an excipient.

Other and further advantages of the present invention will be realizedby those skilled in the art in view of the disclosure set forth herein,and it is intended to include all such advantages as part of the presentinvention, and to be included within the scope of the claims appendedhereto.

BRIEF DESCRIPTION OF THE DRAWINGS

Preferred embodiments of the invention have been chosen for purposes ofillustration and description, but are not intended in any way torestrict the scope of the present invention. The preferred embodimentsof certain aspects of the invention are shown in the accompanyingdrawings, wherein:

FIGS. 1A and 1B, are photomicrographs at 125×magnification ofacetaminophen before and after processing in accordance with the presentinvention;

FIG. 1C is a photomicrograph at 500×magnification of a cross-section ofa sphere shown in FIG. 1A;

FIGS. 2A, 2B, and 2C are schematic representations of the liquiflashprocess in accordance with the present invention;

FIGS. 3A, 3B, and 3C depict one shearlite device useful in the presentinvention;

FIGS. 4A, 4B, and 4C depict a second shearlite device which has beenused in the present invention;

FIGS. 5A, 5B, and 5C depict a third shearlite device used in the processof the present invention;

FIGS. 6A and 6B depict another shearlite device used in the process ofthe present invention;

FIG. 7 depicts an additional shearlite device used in the presentinvention;

FIG. 8 depicts yet another shearlite device used in the presentinvention;

FIG. 9 is a photomicrograph at 50×magnification of a sucrose productprepared in accordance with the present invention;

FIG. 10 is a photomicrograph at 125×magnification of another embodimentof the present invention in which microspheres produced in accordancewith Example II have been coated;

FIG. 11 is a photomicrograph at 50×magnification of ibuprofen shearliteproduct prepared in accordance with the present invention;

FIG. 11A is a graph which depicts dissolution of the ibuprofen shearliteproduct shown in FIG. 11;

FIGS. 12A and 12B are photomicrographs at 50×magnification ofpseudoephedrine prepared in accordance with the present invention;

FIG. 12C is a graph which depicts the dissolution of the product shownin FIG. 12A;

FIG. 12D is a graph which depicts the dissolution of the product shownin FIG. 12B;

FIG. 13 is a photomicrograph at 50×magnification which depicts apseudoephedrine product prepared in accordance with the invention;

FIG. 14 is a photomicrograph at 50×magnification of a dextromethorphanproduct prepared in accordance with the present invention;

FIG. 15 is a photomicrograph taken at 50×magnification of amalgam ofshearlite particles containing a cough and cold treatment formed inaccordance with the present invention;

FIG. 16 is a photomicrograph taken at 50×magnification of spheres formedfrom an amalgam of three (3) active ingredients (also a cough and coldtreatment) in accordance with the present invention;

FIG. 17 depicts a spoon-shaped recipient-dosage delivery system;

FIG. 17A is a sectional view of the delivery system of FIG. 17;

FIG. 18 depicts a multiple-vessel arrangement of recipient-dosagedelivery system;

FIG. 19 depicts another embodiment of the recipient-dosage deliverysystem of the present invention;

FIG. 19A is an elevational view of the embodiment of FIG. 19 showing thebreakaway lid in an open position;

FIG. 20 depicts a view of a multiple-vessel arrangement of therecipient-dosage delivery system of FIG. 19;

FIG. 21 depicts an alternative multi-vessel arrangement ofrecipient-dosage delivery systems;

FIG. 22 depicts a multiple dosage recipient-dosage delivery system;

FIG. 23 depicts an alternative vessel for the recipient-dosage deliverysystem of the present invention;

FIG. 23A depicts the vessel of FIG. 23 with a breakaway lid securedthereto;

FIG. 24 depicts a cup-shaped vessel for use with the present deliverysystem;

FIG. 24A is a sectional view of the vessel of FIG. 24;

FIG. 25 depicts an elongate tubular-shaped vessel for use with thepresent delivery system;

FIG. 25A depicts the vessel of FIG. 25 with the breakaway lid in theopen position;

FIG. 26 is a schematic of a prior art process;

FIG. 27 is a schematic of the process of the present invention;

FIGS. 28a and 28b are schematic representations of a loadedprecompression tablet mold comparing the inventive procedure and theprior art, respectively; and

FIGS. 29a and 29b are schematic representations of a loaded tablet moldduring compression comparing the inventive procedure and the prior art,respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes a method of making a compression tablet.The tablet possesses a rigid structure and a surface which has hardness,i.e., resists penetration and deformation. In the prior art, compressiontablets are produced by a complex arrangement of machinery required toimplement several processing steps and/or to incorporate severalingredients necessary to feed a tablet mold and form a tablet.

The present invention improves the art of tableting because it reducesthe requirement for several processing steps and additional ingredientswhich facilitate flow through the apparatus. Moreover, the process isimproved so that other drawbacks associated with the prior art, such asproduction of fines, are reduced or eliminated.

Tableting machines useful for preparing compression tablets usuallyinclude a die and a punch. Feeding mechanisms direct the granulation tothe die cavity and punches compress the tablet once the granulation hasbeen placed in the die cavity. The tablet press may be a single station(or single punch press) or, alternatively, a multistation (e.g., rotary)press.

In commonly-owned, copending U.S. application Ser. No. 08/194,682, filedFeb. 10, 1994, a material is fed to a tableting machine as a free-formagglomerate in which selected ingredients, such as a medicinalsubstance, and a carrier material are fused together. The free-formagglomerate is distinguished from agglomerates formed from wet and drygranulations, but they are not shearlite particles.

The method of the present invention, however, is implemented by use ofshearlite particles. Shearlite particles are prepared by subjecting afeedstock capable of being transformed to liquiform in the absence of adissolving medium to liquiflash conditions to provide substantiallyunimpeded internal flow. The feedstock contemplated for use in thepresent invention is a feedstock which is capable of being transformedinstantaneously from a solid to a liquid and back to a solid.

It has become known to those skilled in the art of material processing,and, especially to artisans familiar with the technology of the owner ofthe present invention, that "flash flow" refers to conditions oftemperature and force required to transform a solid feedstock to a newsolid having a different morphology and/or chemical structure in theabsence of a heat history. Flash flow can be implemented by "flash heat"processing. The term flash heat is understood to mean a process whichincludes subjecting the feedstock to combinations of temperature,thermal gradients, flow, flow rates and mechanical forces of the typeproduced in the machines referred to herein. The term "flash flow" isdescribed in the co-owned U.S. Pat. No. 5,236,734 issued Aug. 17, 1993,U.S. Pat. No. 5,238,696 issued Aug. 24, 1993, and co-pending U.S.application Ser. No. 07/787,254 filed Nov. 4, 1991, and U.S. applicationSer. No. 07/893,238, the contents of which are incorporated herein byreference.

Flash flow processing known to the art to date contemplatestransformation of feedstock material substantially immediately uponreaching a flow condition whereby the material can move at a subparticlelevel. Liquiflash processing, however, contemplates the reduction of thefeedstock material under conditions of heat and pressure to a conditionwherein any resistance to liquid flow, e.g., viscosity which impedes thepropensity to form liquid droplets, is eliminated. On a macro scale,this condition appears to provide a liquid or liquiform, which terms areused interchangeably herein.

With liquiflash processing, once the feedstock is reduced to a conditionwherein substantially all resistance to liquid flow is removed, shearforce is imparted to the flowing feedstock in an amount sufficient toseparate individual or discrete particles from the mass. The particlesproduced by this separation process, referred to herein asdiscretization, have a size and shape influenced only by the naturalmass separation of the flowing feedstock in the presence of theimpinging shear force. The particles thus formed are referred to asshearlite particles or particulates. If the impinging force is such thatthe separation created is that of a continuous stream, discretizationhas not occurred.

Moreover, the feedstock contemplated for use herein must be capable ofundergoing the required transformation without substantial andpreferably no significant deterioration of the material present therein.

It has been found that liquiflash conditions and the subsequent shearforce imparted thereto in the method of the present invention can beprovided by "barrier processing" which is closely akin to flash heatprocessing as described herein. The flash heat process is a processwherein feedstock can be introduced to a "cotton candy" fabricating typemachine. The spinning machine used to achieve a flash heat process canbe a cotton candy type machine such as the ECONO FLOSS Model 3017manufactured by GOLD METAL PRODUCTS COMPANY of Cincinnati, Ohio.Machines useful in the process of the present invention can be found inco-pending U.S. application Ser. No. 954,257 filed Sep. 30, 1992(incorporated herein by reference), and co-pending U.S. application Ser.No. 08/330,938, filed Oct. 28, 1994, bearing title "Improved Method AndApparatus For Spinning Feedstock Material" (also incorporated herein byreference).

However, in order to implement the liquiflash process as required in thepresent invention, the flash heat apparatus and process have beenmodified. In particular, modifications have been made to deliversufficient energy to the point of transformation of the feedstock, e.g.,the barrier of the spinning head, to liquify it instantaneously.

Considerations for successfully carrying out the objects of the presentinvention reside in the appropriate combination of the followingfeatures:

I. spinner head;

II. liquiflash conditions of temperature and centrifugal force;

III. the character and size of the barrier; and

IV. the character of the ambient conditions adjacent the spinner head.

Spinner heads may be adapted to produce shearlite particles. In general,some of the spinner heads presently available can be modified to providesufficient energy to the feedstock so that in the presence ofappropriate centrifugal force the feedstock transforms to liquiform andis processed substantially instantaneously. Gas (air) resistancediscretizes the feedstock. Elements identified hereinabove can beadjusted to optimize discretization for a particular feedstock.

In order to deliver sufficient energy to achieve liquiflash conditions,the inventors herein have devised configurations of equipment in whichthe heat delivered to the barrier is increased. This requirement hasbeen achieved in apparatus disclosed in commonly owned co-pendingapplication Ser. No. 08/330,938, filed Oct. 28, 1994, which has beenincorporated herein by reference. For example, the number of individualheaters at the periphery of the spinning head can be increased. Anotherway of increasing the thermal energy delivered to the feedstock is byproviding a tortuous path which retards movement of feedstock throughthe barrier on the periphery of the spinning head. Those skilled in theart will appreciate that the combination of increasing the delivery ofheat and retarding flow of feedstock can be combined by various designfeatures to obtain optimum results in the process and, consequently, theproduct. As indicated above, it is intended to cover all such variationsof control over the delivery of heat and the rate of passage of thefeedstock through the barrier as a means of providing liquiflashconditions.

It is preferred that the surface of the spinner head which contacts thefeedstock be coated with a low free surface energy substance. Forexample, a Teflon® based coating will reduce friction between thefeedstock and the surface of the spinner head as the feedstock travelstowards the processing boundary and is forced thereagainst.

Referring to FIGS. 2A, 2B and 2C, the unique phenomenon of liquiflash isschematically depicted. Centrifugal force created in the spinning headflings the feedstock F to the barrier found at the periphery of thespinning head. Heating elements H provided at the periphery reduce thefeedstock to a liquiform condition wherein internal flow becomesunimpeded.

In this liquiform condition, centrifugal force moves the feedstockthrough the openings O between heating elements H provided in theperipheral barrier so that the liquid is exposed to shear force providedby the ambient atmosphere found immediately outside the head. It isbelieved that the flowing feedstock creeps as a layer 1 along thesurface of the exterior of the head until a sufficient volume is builtup in the Laminar flow whereby a tiny mass m of liquiform feedstockbegins to form a generally deformed drop, e.g., a teardrop shape, T,which is met by the atmosphere surrounding the spinning head. The shearforce imparted on the teardrop T being formed by the flowing feedstockseparates a droplet D as a discrete particle by natural mass separation.Natural mass separation at this point is the combination of weight,internal cohesive intra- and intermolecular forces present in theliquiform feedstock and adhesive forces between the liquiform feedstockand the exterior surface of the spinning head. Inasmuch as there is acontinuous flow of feedstock, the teardrops are continuously formed andseparated as discrete shearlite particles D. As a consequence of thisunique process the discrete particles formed thereby have been found tobe highly uniform microspheres, i.e., pearl like spheres having a sizeof not greater than 500 μm, and in most cases having a magnitude ofbetween 25 and 300 μm.

Moreover, the particles produced as a result of this process have beenfound to have a high degree of purity. Thus, drugs which are processedin the absence of any additives whatsoever have been found to experiencea change in morphology which makes them ideal for predictable drugdelivery systems. The drug product can also be augmented by processingwith additional ingredients which are active or inactive, e.g., deliveryingredients, taste masking ingredients, taste modifiers, dissolutionretardants, dissolution expedients, etc.

It is also contemplated that the force required to separate the discreteshearlite particles can be varied by modifying the atmospheresurrounding the spinning head. For example, the apparatus can beoperated in a chamber having multiples of atmospheric pressure, orvirtually no pressure.

The conditions of liquiflash, i.e. principally temperature andcentrifugal force, must be carefully controlled so that on melting to adegree that permits centrifugal force to move the liquiform material toand through the exit orifices, can be accomplished. To obtain this withpure compounds the operator can be guided by its known melting point.With mixtures of materials test melting points can be obtained as arough guide before starting a run. With little experimentation, heaterresistance power can be slowly supplied to a spinner head containing thematerial to be converted into shearlite microspheres and simultaneouslythe rate of spinning of the head can be increased until liquiflashconditions are met. The appearance of microspheres of the desired sizerange verifies that the optimum liquiflash conditions have been met forthis particular material. For instance in Example II, set forth below,acetaminophen powder m.p. 169-170.5° C., has been processed in thedescribed apparatus and the heat was progressively increased toward themelting point of the powder while the spinner head increased to about3600 rpm. Upon melting, and when spheres in the size range of up to 420μ appeared, this constituted the optimum liquiflash conditions for thissize range shearlites of acetaminophen.

DIRECT TABLETING

In prior art processes, the particles are prepared by different methods.A wet granulation method has been shown in FIG. 26 in comparison to theinventive process shown in FIG. 27. In wet granulation procedures,individual powder particles are coated and then formed into agglomerateswhich are called granules. Fusion of the ingredients in prior artprocedures depends in large part on compression of the ingredients. Inthe present invention, amalgamation of the ingredients occurs duringshearlite formation entirely prior to compression.

Referring to FIG. 27, it can be clearly seen that the inventive processeliminates many steps and/or ingredients required to prepare thefeedstock for tableting by the prior art wet granulation method.Moreover, the present invention is also an improvement over traditionaldirect compression tableting procedures. Direct compression has beenknown in the art to define a process by which tablets are compresseddirectly from powder blends of the active ingredient and excipients,such as fillers, disintegrants, and lubricants, which will flowuniformly into a die cavity for tableting by compression. However,traditional direct compression still requires: 1) milling of drugs andexcipients; 2) mixing of the ingredients; and 3) tablet compression. See"Pharmaceutical Dosage Forms," Edited by Lieberman, et al., Vol. 2, Pg112 and 147-161 (1980). The present invention significantly improves thetraditional direct compression method by reducing the separate steps ofmilling and mixing and eliminating the need for excipients to provideadequate flow properties.

Referring to FIG. 27 the process and apparatus of the present inventionare schematically depicted. The process include liquiflash processingwherein the active (and/or inactive) ingredients are combined andshearlite particles are formed. These particles are readily flowable andcan be transported automatically to and through tablet making machinerywithout the necessity of excipient(s), and without need for a coating tofacilitate flow. Moreover, the shearlite particles can be tabletedwithout the requirement of excipient(s) and/or coatings. Thus, theprocess of the present invention is simply (1) the forming of shearliteparticles followed by (2) direct tableting. "Direct tableting" as usedherein means without requirement of excipients and/or coatings, andwithout required additional process steps and/or flow agents, if sodesired. Thus, these other ingredients, and/or steps (such as coatings)may be utilized--not out of necessity, but to engineer or "fine tune"the desired product.

As previously described, it has been advantageously found thatexcipients in the form of the shearlite particles overcome thedisadvantages normally associated with the use of such excipients in anon-shearlite condition. The transformation of an excipient feedstockmaterial to the form of shearlite particles provides the excipient witha shape and size that is compatible with the active shearlite particles.This in turn enables the tableting formulation to maintain a flowabilitythat facilitates direct tableting of the formulation.

Consequently, the mechanical system of the present invention ischaracterized by a unique combination of apparatus characterized by theabsence of devices such as mixers, milling, machines, etc., which aregenerally included in tablet-making systems. Referring again to FIG. 27,the apparatus of the present invention is schematically depicted as ashearlite device (such as those disclosed herein) and a 28 tablet-makingmachine which are simply connected for transfer of shearlite particlesfrom the shearlite device to the tablet-making machine. Transfer ofshearlite particles can be easily accomplished by uninterruptedtransport over a conveyor which connects the shearlite device and thetablet-making machine in FIG. 27. The apparatus of the present inventionis defined herein to mean "in the absence of required additionalapparatus and/or components." Other apparatus or devices, such as acoating device, may be included to obtain desired result, but theseadditional devices are not required.

The advantage of the tableting procedure of the present invention areshown schematically in FIGS. 28a, 28b, 29a and 29b. FIGS. 28a and 29adepict respectively, a filled mold cavity (precompression) and theresults of compressing the feedstock in accordance with the presentinvention. FIGS. 28b and 29b depict, respectively, the prior art processof filled mold cavity (precompression) and the results of compressingprior art feedstock.

In particular, in FIG. 28(a), shearlite particles are shown after theyhave been fed into a compression die. In FIG. 28(b) pre-compressioncomponents of a tablet which have not been subjected to shearliteprocessing are depicted in a die. There are basically three componentsrepresented by +'s, Δ's, and o's. Consequently, the ingredients are notpart of flowable shearlite particles.

In FIG. 28(a), each of the components are part of the shearliteparticles as, for example, an amalgam, while in FIG. 28(b) thecomponents are subject to separation as a result of the feedingmechanisms which direct the particles into the die cavity. Thecomponents are not amalgamate and can agglomerate in "clumps ofcomponents" as displayed in FIG. 29(b).

FIG. 29(a) shows shearlite particles fused together with all componentsremaining in amalgam even under compression. Deformation resulting fromthe force of compression does not force the ingredients out of mixtureor cause "clumping." The homogeneity of the mixture is not disturbed asa result of compression.

FIG. 29(b) shows the compression stroke of the prior art process forcingthe components into clumps. This phenomenon reduces the homogeneity.Consequently, particles will be together in a non-homogeneous mixture.

SHEARLITE FEEDSTOCK

Feedstock which is contemplated for use herein includes saccharidesespecially sugars such as sucrose, sugar alcohols such as mannitol,mixtures thereof, and medicaments which can include active agents aloneor in combination with other active agents or other ingredients. Quitesurprisingly, it has been found saccharides and drugs can be processedwithout deterioration.

Medicaments which can be used in the present invention are varied. Anon-limiting list of active agents which can be included in medicamentsherein is as follows: antitussives, antihistamines, decongestants,alkaloids, mineral supplements, laxatives, vitamins, antacids, ionexchange resins, anti-cholesterolemics, anti-lipid agents,antiarrhythmics, antipyretics, analgesics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, anti-infectives, psycho-tropics, antimanics, stimulants,gastrointestinal agents, sedatives, antidiarrheal preparations,anti-anginal drugs, vasodialators, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, antitumor drugs, anticoagulants, antithromobotic drugs,hypnotics, anti-emetics, anti-nauseants, anti-convulsants, neuromusculardrugs, hyper- and hypoglycemic agents, thyroid and antithyroidpreparations, diuretics, antispasmodics, uterine relaxants, mineral andnutritional additives, antiobesity drugs, anabolic drugs, erythropoieticdrugs, antiasthmatics, cough suppressants, mucolytics, anti-uricemiadrugs and mixtures thereof. Other active ingredients contemplated foruse in the present invention are H₂ -antagonists.

Calcium carbonate (CaCO₃), alone or in combination with magnesiumhydroxide and/or aluminum hydroxide, can be included with otherfeedstock used as a carrier. Thus, such antacid ingredients can be usedin combination with H₂ -antagonists, ibuprofen, ketoprofen, etc., whichare capable of undergoing liquiflash processing.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate,calcium phosphate, citrate ion (acid or salt), amino acetic acid,hydrate magnesium aluminate sulfate, magaldrate magnesiumaluminosilicate, magnesium carbonate, magnesium glycinate, magnesiumhydroxide, magnesium oxide, magnesium oxide, magnesium trisilicate, milksolids, aluminum mono-odibasic or mono-dibasic calcium phosphate,tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodiumbicarbonate, magnesium aluminosilicates, tartaric acids and salts.

Analgesics include aspirin, acetaminophen, and acetaminophen pluscaffeine.

Other preferred drugs or other preferred active ingredients for use inthe present invention include antidiarrheals such as immodium AD,antihistamines, antitussives, decongestants, vitamins, and breathfresheners. Also contemplated for use herein are anxiolytics such Xanax;antipsychotics such as Clozaril and Haldol; non-steroidalanti-inflammatories (NSAID's) such as Voltaren and Lodine;antihistamines such as Seldane, Hismanal, Relafen, and Tavist;antiemetics such as Kytril and Cesamet; bronchodilators such asBentolin, Proventil; antidepressants such a Prozac, Zoloft, and Paxil;antimigraines such as Imigran, ACE-inhibitors such as Vasotec, Capotenand Zestril; anti-Alzheimer agents, such as Nicergoline; and Ca^(H)-Antagonists uch as Procardia, Adalat, and Calan.

The popular H₂ -antagonists which are contemplated for use in thepresent invention include cimetidine, ranitidine hydrochloride,famotidine, nizatidine, ebrotidine, mifentidine, roxatidine, pisatidineand aceroxatidine.

Another aspect of the present invention is a new particulate resultingfrom providing a shearlite particulate substrate in combination of atleast one coating. The substrate can either be a non-active ingredientsuch as a saccharide based material, preferably a sugar such as sucrose,or the substrate can be an active agent, or a combination of activeagents. Thus, in one manifestation of this aspect of the invention thesubstrate can be sugar shearlite particles such as those produced inExample I hereinbelow. Drugs can then be coated thereover either aloneor in combination with other types of coating materials. Furthercoatings can be added as desired. Alternatively, the shearlite particlesthemselves can be an active ingredient or a combination of activeingredients such as those discussed above with respect to the formationof amalgams. As a result of the narrow size range and the unique andreproducible shape of the particle, coating material can be depositedhighly efficiently as very thin even coatings. Consequently, the desiredeffects such as time-release, flavor enhancement or alteration, can beachieved economically and efficiently.

In one specific embodiment of the present invention, the shearliteparticles can be designed to deliver an active ingredient and anantidote. For example, a shearlite particle can be prepared from anactive ingredient, an antidote, a non-active ingredient, or acombination of such ingredients. If the particle is an antidote, it canbe coated with an active ingredient. If the particle is made from anon-active ingredient, it can be coated with an antidote andsubsequently again coated with an active ingredient. In either case acontrolled-release coating can be provided thereover and/or interspersedbetween coatings. Furthermore, another coating such as a muco-adhesivecan be deposited to ensure that the active ingredient is delivered tothe desired part of the body.

A further preferred embodiment of the present invention includesproviding combinations of active ingredients which are designed as acough and cold treatment. Thus, for example, two or more actives can beincluded in the feedstock to form an amalgam which can then be directlytableted to form a tablet or coated and then tableted.

In an additional embodiment, two or more combinations of ingredientsthat prior to the present invention were generally believed to beunstable, interactive or otherwise incompatible may be combined in thefeedstock to produce shearlite particles or may be produced separatelyas shearlite products and coatings and subsequently combined.

"Controlled-release" is used herein to describe a method and compositionfor making an active ingredient available to the biological system of ahost. Controlled-release includes the use of instantaneous release,delayed release, and sustained release. "Instantaneous release" isself-explanatory in that it refers to immediate release to the biosystemof the host. "Delayed release" means the active ingredient is not madeavailable to the host until some time delay after administration.(Dosages are usually administered by oral ingestion in the context ofthe present invention, although other forms of administration are notprecluded from the scope of the present invention). "Sustained Release"generally refers to release of active ingredient whereby the level ofactive ingredient available to the host is maintained at some level overa period of time. The method of effecting each type of release can bevaried.

The patent and scientific literature is replete with various sustainedrelease (SR) methods and formulations. For common methods of obtainingSR systems, see Sustained and Controlled Release Drug Delivery Systems,Robinson, Joseph R., Ed., PP 138-171, 1978, Marcel Dekker, Inc. NewYork, N.Y. Sustained release can be effected by use of coatings, but thepresent invention also contemplates SR by incorporating the necessaryingredients in the shearlite particles themselves. Coatings which do notdetract from the direct tableting aspect of the invention can also beused.

Conventional SR formulations are generally designed to release theiractives over an extended period of time, usually 8-24 hours.Conventional SR formulations use waxes or hydrophilic gums to prolongthe release of the active ingredients. Conventional waxes and waxymaterials used in pharmaceutical formulations are camauba wax,spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol,beeswax, partially hydrogenated vegetable oils, ceresin, paraffin,myristyl alcohol, stearyl alcohol, cetylalcohol and stearic acid. Theyare generally used in amounts of about 10 to about 50% by weight of thetotal formulation.

Hydrophilic gums have also been known to be reasonably effective as SRcarriers for both high-dose and low-dose drugs. Typical hydrophilic gumsused as SR carrier materials are acacia, gelatin, tragacanth, veegum,xanthin gum, carboxymethyl cellulose (CMC), hydroxypropl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethylcellulose (HEC). Generally these materials are present in amounts ofabout 10 to 50% by weight of the final formulation.

Starch USP (potato or corn) can be used as a component incontrolled-release formulation. It generally functions in conventionalapplications as a diluent or as a disintegrant in oral dosage forms.Starch paste is also often used as a binder in these products. Variousmodified starches, such as carboxymethyl starch currently marketed underthe trade name Explotab or Primojel are used as disintegrating agents.The literature discloses that native and modified starches are useful inpromoting rapid release of drugs from solid oral dosage forms.

In all controlled release technologies it is desirable to be able toincorporate the active ingredient in its controlled-release pattern in asingle dosage unit without deteriorating the active ingredient.Moreover, the dosage unit should be able to deliver the system withoutinterfering with its release pattern.

Polymers are also quite useful in the present invention. Solutioncoatings and dispersion coatings can be used to coat the shearliteparticles. Plasticizers are also normally included in both organicsolvent systems and aqueous systems. Some polymers useful for coatinginclude, but are not limited to, the following: methylcellulose(Methocel® A made by Dow Chemical), hydroxypropyl methylcellulose(Methocel® E provided by Dow Chemical or Pharmacoat® provided by ShinEtsu), ethyl cellulose, cellulose acetate, cellulose triacetate,cellulose acetate butyrate, cellulose acetate phthalate, celluloseacetate trimellitate (provided by Eastman Kodak), carboxymethylethylcellulose (Duodcel®/Freund), hydroxypropyl methylcellulose phthalate,polymethacrylic acid-methacrylic acid copolymer (Type A 1:1 Eudragit®L100; Type B 1:2 Eudragit® S100; and Type C 1:1 Eudragit® L100-55,aqueous dispersion 30% solids, Eudragit® L30D), poly(meth)acryl ester:poly(ethyl acrylate, methyl methacrylate 2:1), Eudragit® NE30D aqueousdispersion 30% solids, polyaminomethacrylate Eudragit® E100,poly(trimethylammonioethyl methacrylate chloride)-ammoniomethacrylatecopolymer, Eudragit® RL30D and Eudragit® RS30D.

Plasticizers used in the above solvent plasticizers which may be used inthe present invention are as follows: diethyl phthalate, dibutylphthalate, triethyl citrate, glycerol triacetate, and dibutyl sebaccate.

Aqueous polymeric dispersions useful in the present invention includeEudragit® L30D and RS/RL30D, and NE30D, Aquacoat brand ethyl cellulose,Surelease brand ethyl cellulose, EC brand N-10F ethyl cellulose,Aquateric brand cellulose acetate phthalate, Coateric brand Poly(vinylacetate phthalate), and Aqoat brand hydroxypropyl methylcelluloseacetate succinate. Most of these dispersions are latex, pseudolatexpowder or micronized powder mediums.

Plasticizers which can be used include, but are not limited to, thefollowing: propylene glycol, polyethylene glycol (PEG 400), triacetin,polysorbate 80, triethyl citrate, diethyl d-tartrate.

For example, enteric release agents and/or coating broadly includeporous cellulose acetate phlatate (provided by Eastman Kodak) incombination with beeswax for blocking its pores. Other combinationsinclude shellac and ethyl cellulose mixtures, and shellac, methylalcohol and castor oil mixtures. Also an ethylene-vinyl acetatecopolymer can be used, such as duPont ELVAX® 40.

Other enteric substances used in or with the present invention arepolyacrylate substances bearing many carboxyl groups in their moleculesas part of a shearlite amalgam or as a coating. Examples are methacrylicacids-ethyl acrylate copolymers [manufactured by Rhom-Pharma Co. (WestGermany) Eudragit® L300D], methacrylic acid-methyl methacrylatecopolymer (Eudragit® L or Eudragit®S), hydroxy propyl methyl cellulosephthalate (manufactured by Shin-Etsu Chemical Co., HP-50, HP-55,HP-55S), hydroxypropyl methyl cellulose acetate phthalate (manufacturedby Shin-Etsu Chemical Co., AS-LG, AS-LF, AS-MG, AS-MF, AS-HG, AS-HF),carboxymethyl ethyl cellulose [manufactured by Fruent Industry Co.(Japan)], cellulose acetate phthalate, and vinyl methyl ether malicanhydride copolymer [manufactured by GAP Co. (US), AN-139, AN-169].

Preferably, Eudragit® L, Eudragit® S and HP 55 are employed, becausethey have high contents of carboxyl groups with high safety.

In general, processes known in the art for preparing coated particlescan be used. For example, process for preparing particles as disclosedin U.S. Pat. No. 4,971,805 are contemplated for use with the shearliteparticles. These processes are incorporated herein by reference and thedisclosure set forth in the '805 patent is specifically incorporatedherein by reference. See also U.S. Pat. No. 4,948,622 to Kokubo, et al.which is incorporated herein by reference.

In the Kokubo, et al. '622 patent, the granules, beads and tablets werecoated with a dispersion of cellulose ether and then subjected to waxtreatment with heating to form a masking layer of wax. It is alsocontemplated to use waxes as a coating material in the presentinvention. As previously mentioned waxes include carnauba, beeswax,vegetable waxes, animal waxes (spermaceti) and synthetic wax such ascarbowax, e.g., polyether. Also contemplated for use herein includeshydrocarbon waxes such as paraffins and petrolatums. Higher alcoholssuch as cetyl alcohol and stearyl alcohol, higher fatty acids such asstearic acids, esters of higher fatty acids, fatty acids esters ofglycerins such as beaf tallow, lard, hardened soybean oil and hardenedcastor oil and polyethylene glycols such as PEG-6000 and PEG-20,000 aswell as various commercial products sold under the trade names of LubriWax-100 prectrol, which is a mixture of mono-,di-and tripalmitates ofglycerin, and the like. These wax materials can be used either singly oras a mixture of two kinds or more according to the need.

The present invention also contemplates the use of fats in the productsproduced by the present invention. Fats include esters of higher fattyacids, e.g., glycerides of C₁₀₋₂₄ fatty acids, alcohols, salts, ethersor mixtures thereof. They are classed among the lipids. It is alsocontemplated that emulsifiers to be included in conjunction with thefats. Emulsifiers include salts of ethanolamines with fatty acids andsulfated fats and oils. Preferred fats include compositions which havemono-,di-or tri-glyceryl esters of long chain of fatty acids. Theseinclude but are not limited to stearates, palmitates, laureates,linoleates, oleates, and residues or mixtures thereof having meltingpoints greater than 50° C. U.S. Pat. No. 5,213,810 is directed tocompositions including these materials and the '810 reference is herebyincorporated.

The coating process can be effected by spray coating with multiple fatsor waxes onto the shearlite particles.

Such coatings can typically be used for taste-masking andcontrolled-release. As a result of the high uniformity and narrow sizedistribution, shearlite particles permit the use of substantially lesscoating materials to produce the intended effect. Thus, with a singlecomplete but thin coat, a high degree of taste-masking and efficientcontrolled-release can be effected.

In order to illucidate this benefit, an example has been includedhereinbelow (Example XII) wherein ibuprofen feedstock is coated andcompared to ibuprofen shearlite particles which are coated. The twocoated ibuprofen materials were compared for taste. The coated ibuprofenwhich was not converted to shearlite particles was unacceptable, whereasthe processed ibuprofen (subsequently coated) was found to be highlyacceptable. Microscopic examination of the unprocessed ibuprofenrevealed agglomerated needles of ibuprofen which had varying thicknessesof coating. To the contrary, the shearlite ibuprofen particles displayeda uniform thickness of coating which is ideal for taste-masking andcontrolled-release.

The present invention contemplates a combination of a low melting fat orwax with an active ingredient which has been transformed to shearliteparticles. The material is processed and fed to direct tableting. Thefat or wax can also be used as a coating.

In yet another example of the unique advantage provided by the presentinvention, an antidote material can be transformed to shearliteparticles in conjunction with an active ingredient. Both the antidoteand the active ingredient may or may not include controlled-releaseagents to enhance dissolution or to retard dissolution. Any combinationof active in antidote can be formulated depending on the need of thepractitioner. The active agent can be the shearlite particle while theantidote can be the coating. Additional coatings can be included in amultiple coated product to provide active and antidote. Any combinationof these agents suitable for the desired purpose are contemplated ascovered by the present invention.

Furthermore, liquiflash processing and products from industrialchemicals which benefit from reduction in dusting and better flowproperties are contemplated as part of the present invention. Suchindustrial chemicals include, but are not limited to, the following:phenol, styrene, butylated hydroxy anisole (BHA), tert butylhydroxyhydroquinone (TBHQ),parabens, hydroquinone, insecticides, herbicides,combinations of insecticides and herbicides, anti-fungals and otheragents which suffer from dusting which may cause explosion or mayendanger personnel by contact therewith.

As described herein and as illustrated in the following examples, theshearlite particles produced in accordance with the present inventionexhibit unexpectedly high flowability. That is, the shearlite particlesproduced under liquiflash conditions flow easily and evenly under theforce of gravity. "Flow easily and evenly" is used to mean that greaterthan 95%, preferably greater than 98%, and more preferably substantially100%, of the shearlite particles will flow away from apreviously-confining boundary (e.g., a wall of a vessel) without anysignificant adherence of the particles to the boundary. The particleswill also flow away from the boundary without any significant caking ordusting of the particles. More to the point, the particles will flowaway from such boundary at a low angle of repose. (The angle of reposedefines the angle required to induce flow of the particles from a level"at rest" position.) The particles of the present invention exhibit anangle of repose of less than about 45°, and more preferably less thanabout 30°.

As will be apparent to those skilled in the art, the ability to converta non-flowable material into a flowable material improves certainexisting applications and processes, and also creates entirely newapplications. Thus, any substance capable of being subjected toliquiflash conditions may be processed to provide shearlite particlesexhibiting enhanced flowability, without the negative propertiescommonly associated with multiparticulates such as adherence toboundaries, caking and/or dusting. Moreover, it is contemplated thatsubstances which may not themselves be subjected to liquiflashconditions can be carried by shearlite particles of a compatiblematerial.

According to the present invention, the processing of a substance, e.g.,a bio-affecting agent, produces shearlite particles which may thereafterbe packaged for subsequent delivery to a recipient, i.e., a patientrequiring administration of the bio-affecting agent. Of course, it iscontemplated that other substances in addition to bio-affecting agentsmay be subjected to liquiflash conditions to produce shearlite particleswhich can thereafter be packaged in suitable containers. These othersubstances include sucrose, flavor enhancers and various industrialchemicals and the like. In one particularly preferred embodiment, abio-affecting agent is delivered with and/or carried by shearliteparticles of sucrose and/or various flavor enhancers.

As described hereinabove, there are many applications, particularly inthe medical field, where the ability to accurately deliver a metereddose of a multiparticulate substance directly to a recipient in theabsence of a conventional delivery format is highly desirable. However,the very fact that a substance is reduced to a multiparticulate form hasin the past necessitated the need for use of a mechanized deliverydevice, e.g., a low velocity spray apparatus, because multiparticulatessuffer from various physical limitations such as adherence toboundaries, caking and dusting. Thus, it becomes impractical and/orimpossible to consistently and accurately deliver a metered dosage of amultiparticulate substance in the absence of a mechanized deliverysystem. As also discussed above, the use of mechanized delivery deviceshas certain disadvantages associated therewith including: i) the need tocarry the device, ii) size and cost of the device, iii) sterility of thedevice, iv) accuracy and consistency of delivery of the device, and v)other various inherent limitations.

It has been discovered herein that shearlite particles produced by thesubjecting of a bio-affecting agent to liquiflash conditions provide thebasis for a novel recipient-dosage delivery system. This deliverysystem, which entails contact of a metered dose of shearlite particlesof a bio-affecting agent and a recipient, e.g., an oral cavity of ahost, is produced by the packaging of such shearlite particles in asuitable vessel. This vessel is preferably bifunctional in natureinasmuch as the vessel provides for 1) sterile storage and readytransportation of the packaged particles, and 2) serves to deliver theparticle to the recipient (i.e., the particles are delivered directlyfrom the vessel to the recipient without use of a mechanized device orinstrument).

As mentioned, a metered dose of shearlite particles is packaged in thevessel. Thereafter, the vessel is opened and the shearlite particles areadministered to the recipient, e.g., to the oral cavity of the host.(The term "administer" as used herein is defined as meaning that greaterthan 95%, preferably greater than 98%, and more preferably substantially100%, of the shearlite particles are transferred from the vessel to therecipient, this transfer occurring under the force of gravity). In oneparticular application, the recipient opens the vessel andself-administers the contents thereof, namely, the shearlite particlesof bio-affecting agent, by positioning the vessel adjacent to his or hermouth and holding the vessel at an angle of repose whereby the shearliteparticles flow from the vessel into the oral cavity of the recipient,whereupon such particles are immediately dissolved and absorbed by thebody of the recipient.

The shearlite particles are preferably packaged in a bifunctionalvessel. These vessels, as further described hereinbelow, may be producedfrom various well known manufacturing processes such as injectionmolding, blow molding and die forming, thus providing a suitablecontainer for sterile storage of the shearlite particles. In thisregard, the vessels are readily transportable by the recipient, and arediscarded after use. The vessels may be formed from various materialsincluding high density polyethylene, polypropylene, polystyrene, acetylbutyl styrene, propyl acetate and polyethylene terephthalate. In oneembodiment, the vessel is preferably formed from a material which iselectrically compatible with the shearlite particles inasmuch as contactbetween the vessel and the shearlite particles does not tend to createand/or retain a static electric charge. Alternatively, the vessel and/orshearlite particles, either before or after packaging of the particles,may be subjected to a static discharge operation.

The vessel is preferably shaped to facilitate delivery of the particlesdirectly from the vessel to the recipient, e.g., the vessel may includea spout and/or lip which directs and thus facilitates the flow of theparticles from the vessel. The vessel is preferably sealed closed with aremovable closure whereupon removal of the closure by the recipientallows access to the packaged particles for delivery thereof. Forexample, peel-away backings or covers formed of aluminum foil laminatedwith polyethylene or mylar film may be adhered around the rim of thevessel following filling of the vessel. Alternatively, variousbreak-away lids or caps can be used to close the vessel. Of course, itis contemplated that other suitable closures may be utilized herein.

In one particularly preferred embodiment, a plurality of vessels aredetachably secured to one another thus providing a multi-vesseltransportable package of recipient-dosage delivery systems. Suchmulti-vessel arrangements facilitate the packaging of the product at themanufacturing level, facilitate dispensing of the medicaments, and alsofacilitate subsequent handling and transportation of the vessels. Forexample, a multi-vessel arrangement of seven vessels would allow aphysician to readily prescribe a week's supply of a particularmedicament (assuming the medicament is administered one time per day).In addition, the multi-vessel arrangement allows the recipient toreadily transport the medicament.

In another particularly preferred embodiment, at least two adjacentvessels may be arranged so as to allow simultaneous removal of theirrespective closures for simultaneous delivery of the metered dosescontained in such vessels. For example, it may be practical toseparately package two different medicaments which are to besimultaneously administered by the recipient. In non-medicalapplications, it may be desirable to separately package and thereaftersimultaneously deliver two industrial chemical or two active ingredient,e.g., a laundry enzyme and a laundry bleach.

As mentioned, the shearlite particles produced under liquiflashconditions exhibit enhanced flowability. More particularly, theseshearlite particles are capable of undergoing restricted flow under theforce of gravity. Thus, the shearlite particles not only will flow froma generally open-sided vessel, but will flow through a restrictedpassage, e.g., a funnel-shaped apparatus. This unexpected ability toundergo restricted flow is significant in that it allows the shearliteparticles to be packaged in a vessel having an elongated neck orotherwise restricted flow passage leading therefrom which facilitatestransfer of the particles from the vessel to the recipient. As describedhereinabove, multiparticulate substances which have not been subjectedto liquiflash conditions do not exhibit restricted flow capability, andthus are not suitable for packaging in a restricted flow vessel, or anyother vessel for that matter, because the non-processedmultiparticulates adhere to the walls of the container, cake, dustand/or generally provide inadequate transfer of the packaged medicamentfrom the vessel to the recipient. The restricted flow capabilities ofthe shearlite particles of the present invention are also significant inthat restricted flow passages are found in various commercial machinery.That is, the ability of the shearlite particles to undergo restrictedflow ensures that such particles may be readily transferred throughand/or along the machinery.

Referring to FIGS. 17 and 17A, shearlite particles of a bio-affectingagent, e.g., a medicament, may be administered to a recipient via aspoon-shaped vessel 100. Vessel 100 includes a particle-storing bowl 102sized to receive and hold a metered dose of shearlite particles 104 of adesirable bio-affecting agent and a handle 106 configured to allowmanipulation of the vessel by the recipient. The vessel further includesa peel-away backing 108 which is sealingly secured to a rim 110surrounding bowl 102 following the filling of the bowl with the metereddose of shearlite particles. Backing 108 preferably includes at leastone corner tab 112 which allows the recipient to easily peel-away thebacking and access the packaged particles.

In one preferred embodiment, as shown in FIG. 18, a second vessel, i.e.,vessel 100', is fabricated together with vessel 100, thus providing aplurality of interconnected recipient-dose delivery systems, i.e., amulti-vessel transportable package 114. (Of course, it is contemplatedherein that any number of vessels may be fabricated together in integralfashion.) Vessel 100' includes a second particle-storing bowl, i.e.,bowl 102', affixed to a handle 106'. Handles 106 and 106' are attachedalong a score line 116 which allows one of the bowls to be readilyseparated from the multi-vessel arrangement and thereafter discardedonce the metered dose of shearlite particles packaged therein has beendelivered to the recipient. The multi-vessel transportable packagefacilitates dispensing and subsequent transportation of therecipient-dosage delivery systems by the recipient. Multi-vesseltransportable package 114, which includes two recipient-dosage deliverysystems, is particularly suitable for patients who are required toadminister two daily dosage of a medicament. An individualself-administers one metered dose of medicament (the first dailyadministration), breaks off the empty bowl along score line 116, andretains the remaining sealed bowl of medicament for the subsequentsecond daily administration.

To administer the metered dosage of medicament contained in bowl 102 ofvessel 100, the individuals grasps tab 112 of backing 108 and peels awaythe backing from rim 110, thereby exposing the previously-packagedparticles. The individual then empties the contents of the bowl into hisor her mouth. Because of the enhanced flowability exhibited by theshearlite particles of the present invention, the particles readily flowfrom the bowl into the individual's mouth when the vessel is tipped at asuitable angle of repose, typically less than 45°. Moreover, this flowis accomplished without adhering of the particles to the walls of thebowl, caking and/or dusting of the particles and, further, results inthe complete emptying of the bowl, that is, substantially 100% of theparticles are transferred from the bowl to the recipient.

An additional storage and delivery vessel, i.e., vessel 118, is shown inFIGS. 19 and 19A. Vessel 118 includes a flask-shaped particle-storingbody 120 having an elongated neck 122 connected thereto. After body 120is filled with a metered dosage of shearlite particles, the vessel issealed closed with a backing 124 (shown in FIG. 19A) secured around arim 126 surrounding the flask-shaped body. The vessel is preferablyscored along score line 128, thus allowing a user to readily "break off"the lid and thereby access the packaged particles.

Flask-shaped vessel 118 is particularly suitable for multi-vesselpackaging, as shown in FIG. 20. That is, a plurality of interconnectedvessels which allow ready separation may be simultaneously fabricated.More particularly, a multi-vessel transportable package 130 includes aplurality of vessels 118 which are detachably secured to one anotheralong score lines 132. As mentioned, the use of multi-vessel packagingfacilitates the dispensing and subsequent handling of the deliverysystems. For example, the delivery systems may be fabricated intransportable packages of any convenient size, e.g., 7 delivery systems(a one week supply).

An alternative multi-vessel transportable package, i.e., package 134, isshown in FIG. 21. In the disclosed arrangement, the user removes avessel 136 from the package 134, thus leaving the remaining sealedvessel for subsequent use. Inasmuch as the vessel includes a break-awaylid 138 attached to a centrally-disposed tab 140 along score lines 142,the removing of the vessel from the pack results in the opening of thevessel. The user is thus ready, upon removal of the vessel, the deliverto contents of the vessel.

In one particularly preferred embodiment, as shown in FIG. 22, amulti-dosage delivery system 144 is provided (as compared to the singledosage delivery systems discussed above). The multi-dosage deliverysystem includes a plurality of vessels arranged to allow forsimultaneous opening of multiple vessels and subsequent simultaneousdelivery thereof. As shown, multi-dosage delivery system 144 includestwo particle-storing bodies 146. Each of bodies 146 includes anelongated neck 148 connected thereto. In turn, each neck is sealedclosed with a break-away lid 150. The lids are secured to a common tab152, which upon application of pressure thereto simultaneously breaksoff both of the lids, thus allowing the user to simultaneously accessand thereafter deliver the shearlite particles packaged in each of thevessels. Applications which may require simultaneous delivery of aplurality of metered dosages include among others various asthmamedicaments.

Referring to FIGS. 23 and 23A, the shearlite particles may be packagedin a discrete vessel, i.e., vessel 154. Vessel 154 includes aparticle-storing body 156 having an elongated restricted flow neck 158connected thereto. The vessel may be sealed with a peel-away cover 160,although alternative closures such as twist-off caps may also be used.One particularly preferred embodiment (shown in FIG. 23A) includes abreak-away lid 162 adopted to break off of neck 158 along score line 164upon application of pressure thereto. Lid 162 preferably includes afinger-engaging tab 164 to facilitate breakage of the lid from the neck.Once vessel 154 has been opened, the recipient thereafterself-administers the shearlite particles by tipping the vessel andallowing the shearlite particles to flow through the neck and into hisor her mouth.

In addition, the shearlite particles of the present invention may bepackaged in any number of additional manners, including but not limitedto a cup-shaped vessel 166 as shown in FIGS. 24 and 24A and an elongatetubular-shaped vessel 168 as shown in FIGS. 25 and 25A.

SHEARLITE DEVICE

Referring to FIGS. 3A, 3B, and 3C, a first spinning head has been shownwhich can be used in the liquiflash process. The assembled head 10 isdepicted in FIG. 3A. This head is of the type which is disclosed in U.S.Pat. No. 07/954,257 filed Sep. 30, 1992 and its continuation in partapplication bearing Ser. No. 08/192,133 filed Feb. 4, 1994 (both ofwhich are incorporated herein by reference).

Referring to the spinning head shown in FIG. 3A, a heating element(s)are depicted as continuous cable 12 which is helically wound thereabout.The cable heating element can consist of several cables or even just onecable which is continuously wound around the periphery of the head 10.The embodiments disclosed in the two (2) applications referred to abovehave certain characteristics, such as slits, etc., for flash flowprocessing.

In the present invention, however, the small openings in the head areachieved by lacing a shim 14 between the coils of the heater 10. FIG. 3Cis a diagrammatic sketch of this embodiment. The shim material 14 ispreferably a very thin strip of food grade metal such as stainlesssteel. The thickness of the shim can be from 0.001 to 0.006 inch inthickness. Preferably, the thickness of the shim is about 0.002 inch.The shim can be about 0.100 inches wide. The lacing can be provided atseveral locations around the perimeter of the head. Furthermore, tefloncoating insulators can be provided in conjunction with the heating cablein order to reduce the friction of the surface of the heating elements.

Yet another embodiment of apparatus which can be used in the presentinvention is shown in FIGS. 4A, 4B, and 4C. The apparatus of the typeused herein has been disclosed in U.S. application Ser. No. 08/226,234filed Jun. 27, 1994 (which is incorporated herein by reference).

Referring to FIGS. 4A-C, a spinning head silhouette 16 is shown havingspaced apart protruding ribs 17 in which tiny openings have beendrilled. Preferably the openings are on the order of 0.020 inches indiameter. Referring to FIG. 4B, a cut-away section of the head of FIG.4A is shown with the holes 18 in the raised ribs 17. A heating element19 can then be wound around the outside surface of the head 16 in orderto provide heat sufficient to melt the feedstock on the interior surfaceof the spinning head.

The spacing and configuration of the holes can be adjusted by thoseskilled in the art to achieve the results which are desired. Adiscussion of this has been fully set forth in the above-identifiedpending U.S. application. Other variations of this embodiment includingsize of holes, spacing between the holes, and shape of the openingsthrough the head can be varied depending upon the application. It hasalso been found that the openings in the configuration shown in FIGS.4A-C are ideally provided by drilling with a laser beam.

Yet another apparatus used in the present process is shown in FIGS. 5A,5B, and 5C. The apparatus shown in these figures is of the typedisclosed in commonly owned copending U.S. application Ser. No.08/330,938, filed Oct. 28, 1994, and having the title "Improved Methodand Apparatus For Spinning Feedstock Material." In FIG. 5A, a spinninghead 20 is shown with upright closely spaced heating elements 22. In apreferred embodiment, electrical current can be provided to eachelement. In this way, a high degree of control can be maintained overthe heat supplied to the processing barrier. Furthermore, the elementscan be spaced as closely together as possible in order to provide arestricted passageway for passage of liquiform material.

In another preferred embodiment as shown in FIG. 5B, a continuous screencan be interwoven between the heating elements in order to affect thesize of openings through the barrier and also to provide a barrier withrelief which enhances drop formation. It has been found that screenswith 60 mesh and 30 mesh can be used. The actual opening size, e.g.,mesh, can be selected by the artisan.

In yet another embodiment, each heating element 22 can be individuallyprovided with a shim 24 which further reduce the size between theheating elements. As a result of using the shims, opening sizes on theorder of 0.005-0.007 inch can be reduced to openings on the order of0.002 inch.

In each of the embodiments, the head has a diameter of about 3 inches.The apparatus in the present invention has currently been run at arotational velocity in the area from around 3,000-5,000 rpm. The actualspeed can vary from as low as 500 rpm to as great as 100,000 rpm. It iscontemplated that many commercial embodiments will be run in the area of35,000-40,000 rpm. Once again, the size of the head and the rotationalspeed of the head will depend on the desired results, and other factorssuch as the size and nature of the feedstock, and the ambient atmosphereadjacent to the spinning head.

Referring to FIGS. 6A and 6B, a further modification of spinner head 10,particular useful with pharmaceutical product, as described above, isshown. Spinner head 10 is modified in a manner similar to the embodimentset forth above wherein a number of tubular heating elements 30 havebeen provided. However, in order to narrow the opening through whichfeedstock materials expelled, this embodiment employs individual modularblocks 32 which fit over heating elements 30.

Each modular block 32 includes a metallic heat conductive body having acentral cylindrical passage 34 therethrough which is constructed andarranged to accommodate individual tubular heating elements 30. Eachmodular block 30 also has a generally trapezoidal cross-section having asmaller wall 36 which faces inwardly toward the feedstock chamber and anopposite wider outer wall 38. In a preferred form, the outer wall 38 mayinclude angular surface 39, which provides for longer opposed side walls40 and 42 without increasing the mass of modular blocks 30. The modularblocks 30 can be slipped over tubular heating elements 30. As shown inFIG. 6B, walls 40 and 42 form radially directed slots between adjacentmodular blocks 32 through which feedstock material may be processed andexpelled in a manner similar to that explained above with respect to theprevious embodiments. The radially directed slots can be adjusted toalter the size of the passage through which the feedstock material isexpelled.

As shown in FIG. 6B, blocks 32 can be rotated about tubular heatingelement 30 (see arrows B) to cant or twist the blocks, thereby changingthe spacing and/or direction of the slots. The rotation of blocks 32 canbe accomplished individually or may be rotated in unison with anappropriate mechanism (not shown). With such a mechanism, modular blocks32 may move in a manner similar to an iris diaphragm of a camera toincrease or decrease the size of the passage defined by the slots.

A further construction of block 50 is shown in FIG. 7, where transverseslots are formed. Modular block 50 can include a body formed to have aseries of vertically spaced horizontally extending fins 52. Modularblock 50 can be constructed so that one set of fins 52a interleave withan adjacent set of fins 52b of an adjacent modular block 50. In thismanner a series of vertically spaced transverse slots 54 are formedthrough which feedstock material may be processed.

Referring now to FIG. 8, still further embodiment of the spinner head ofthe present invention is shown. Spinner head 55 of the present inventionincludes a generally circumferential array 55a of horizontally disposedtubular heating elements 56. A set of vertically spaced horizontallyextending heating elements 56 can be positioned between an adjacent pairof vertically extending support elements 57. Each of support elements 57can be positioned and spaced in circumferential fashion about base 55b.Appropriately, configured retaining openings 55c are provided toaccommodate support elements 57.

Horizontally disposed tubular heating elements 56 can be of similarconstruction to tubular elements previously described hereinabove. Allor selected ones of tubular heating elements 56 may be individuallypowered in accordance with the present invention. It is alsocontemplated that vertical support elements 57 in additional tosupporting horizontally extending tubular heating elements 56 may alsoprovide a common power bus to energize the individual tubular heatingelements. Vertical support elements 57 include appropriate openingsspaced therealong which accommodate the ends of tubular heating elements56 therein in an interference fit such that the securement between thetubular heating elements 56 and the vertical support elements 57 isachieved under both ambient and running temperatures. The space isbetween adjacent horizontally disposed tubular heating elements 56 canbe adjusted to vary the openings through which feedstock material isprocessed.

It is further contemplated that tubular heating elements of uniform sizeand configuration or of differing size and configuration may be employedwithin the same spinner head. An arrangement of the same or differentsize tubular heating elements allows the spinner head to be staticallyand/or diametrically balanced. As described above with respect to thespinner head having vertically disposed tubular heating elements,horizontally positioned tubular heating elements 56 of the presentembodiment can be canted are skewed with respect to support elements 57.

Furthermore, even though FIG. 8 shows one circumferential arrangement ofarray 55a, other arrangements are also within the contemplation of thepresent invention. Further, plural concentric sets of arrays ofhorizontally disposed tubular heating elements are within thecontemplation of the present invention.

The embodiment shown in FIG. 8 also has particular utility with respectto pharmaceutical products since the individual tubular heating elements56 supported between a common bus such as vertical support element 57can be easily removed for cleaning as necessary in the processing ofpharmaceutical products.

Those skilled in the art will appreciate that other factors willdirectly affect the size and shape of the apparatus, and is intended toinclude all variations that come within the spirit of the invention asdefined in the appended claims.

EXAMPLES Example I Sucrose Spheres

In the first example, the apparatus disclosed in FIG. 5A was used in theliquiflash process for transforming sucrose. The opening betweenadjacent heating elements in the apparatus shown in FIG. 5A was 0.20inches. The head was spun at 3600 rpm as it was heated to 180° C.

As the temperature reached its peak, sucrose was subjected to liquiflashconditions and exited the spinning head as a result of centrifugalforce. Solid spheres (i.e., shearlite particles) were formed whichranged in size from about 100-200 μm in diameter. The very unique anduniform size distribution is clearly shown in the photomicrograph hereinat FIG. 9. The magnification of Figure is 50.

In this particular case, the size of the rock candy prevented passagethrough the barrier and provided delay at the barrier sufficient tocause sucrose to transform to liquiform and be instantaneously processedto the highly uniform microspheres depicted in FIG. 9. These spheres aresubstantially solid throughout, and can be used in a variety of ways,such as a substrate for depositing of material thereon.

It should be noted that microspheres having a diameter of from about5-50 μm and preferably around 25 μm are excellent for use in conjunctionwith chocolate. Very small and highly uniform microspheres enable thepractitioner to provide a highly acceptable low fat chocolate product.Thus, the processing of sucrose, such as in the form of rock sugar,could be used quite effectively to provide an ingredient for thepreparation of a chocolate product.

Example II Acetaminophen Spheres

In this example, acetaminophen was processed using the apparatus showedin FIG. 5B wherein the screen was a 60 mesh screen positioned inserpentine fashion between adjacent heating elements. Acetaminophenpowder (melting point 169-170.5 ° C.) was fed to a spinning head run atabout 3600 rpm. While the feedstock was subjected to centrifugal force,the temperature was raised until the acetaminophen powder was reduced toliquiform. The force generated by the spinning head expelledacetaminophen out of the spinner head, and impelled it through the 60mesh screen. The product was permitted to free fall below the head adistance of from about 6 to 8 feet.

During this transition, fine spheres all of which were less than about420 μm, were formed. 4.33 kilograms of this material was passed througha 40 mesh screen and 1.39 kilogram of the product was retained.

The feedstock, and product resulting from this experiment have beenshown herein in FIGS. 1A, 1B, and 1C. In FIG. 1B, a photomicrograph ofthe feedstock is shown at 125×magnification. After processing, theresulting product was collected and a photomicrograph taken which isshown in FIG. 1A. As can be seen, a highly consistent and very uniformspherical product was produced. Comparing the product shown in FIG. 1Ato the feedstock at FIG. 1B, the skilled artisan can readily ascertainthe enhanced predictability and processability which is provided as aresult of the present invention. FIG. 1C is a photomicrograph at500×magnification taken of a cross section of a sphere shown in FIG. 1A.As can be seen, the sphere is substantially solid throughout havingvirtually no openings or voids therein. Once again, this product enablesthe artisan to provide a highly efficient drug product which can be usedreadily in delivery systems.

Example III Coated Acetaminophen Spheres

Acetaminophen spheres prepared in Example II, were then coated with aformula consisting of 2.5% Eudragit® E100, 7.5% ethocel in a solventhaving acetone and methanol in 8 to 1 ratio. Eudragit® is a polymer ofmethacrylic acid and methyl methacrylate available from Rohm Pharmo,Wetterstadt, Germany.

The finished product provided 568 grams of finely coated acetaminophenbeads. The coated product of the present example has been shown hereinin FIG. 10 at 125×magnification. A very uniform coated product has beenshown which can be easily used in feeding the coated active ingredientto machinery for tabletting and for the purpose of filling capsules.

Thin, uniform coatings such as that provided herein results in much lesscoating material required to obtain better resulting taste masking andcontrolled release. As a result of the monodispersed characteristic ofthe present product, there is less loss of product as a result ofoversize material.

Coating in general is tremendously enhanced by providing a uniformlydispersed microsphere of the present invention. For example, influidized-bed type coating, the equilibrium condition established in thefluidized bed has a tendency to retain particles having a similar sizefor consistent and efficient coating. Thus, large and small particlesoutside the range of the uniform particle size leave the bed duringcoating. In that case, the active ingredient must be recycled andreprocessed to obtain the active ingredient for coating. In the presentinvention, non-uniform sizes are virtually eliminated.

Example IV Ibuprofen Spheres

Using the same apparatus as shown in FIG. 5B, with a 60 mesh screen,ibuprofen was processed in accordance with the present invention.

An ibuprofen powder feedstock was fed to the spinning head and the headwas rotated at about 4800 rpm while the heating elements were raised toa temperature which produced the liquiflash conditions. The feedstockalso consisted of 15% Compritol 888 ATO and 5% Gelucire 50/13.(Compritol 888 ATO is a glycerol behenate NF made available byGattefosse S.A., a French company. Gelucire is surfactant also availablefrom Gattefosse S.A.).

The spinning head forced the material through the screen and the productwas permitted to free fall a distance of from 6-8 feet below thespinning head. The product collected is shown in the photomicrograph ofFIG. 11 which has a magnification of 50×. As can be seen from FIG. 11,the spheres have a highly consistent particle size ranging from about50-200 microns in diameter.

The product was also subjected to dissolution testing to determine thetime required for dissolution of the active ingredient. The monograph isprovided by the U.S. Pharmacopoeial Convention, Inc. in the U.S.Pharmacopoeial National Formulary Monograph For Ibuprofen DissolutionStudy, U.S. 23 NF 18, page 786 (1995). The results have been shown inFIG. 11A. At a composition level of 80% ibuprofen, it can be seen thatthe time for dissolution of most of the ibuprofen occurred at about 15minutes and virtually total dissolution occurred at around 20-25minutes. These results show high predictability for delivery to abio-system by use of microspheres produced in accordance with thepresent invention.

Example V Ascorbic Acid Spheres

In this Example, ascorbic acid was processed by the liquiflash processusing the apparatus described in FIG. 5C. As a result of the short brassveins having a thickness of about 0.006 inches surrounding each of theheating elements, gaps of 0.002 inches were provided. Moreover, the headwas positioned 10 feet from the collecting surface to permit anunobstructed formation and solidification of shearlite particles inaccordance with the present invention.

Ascorbic acid powder was fed into the spinner revolving at about 1800rpm while the head was heated to a point at which the powder was changedto liquiform for purposes of liquiflash processing. Fine beads wereexpelled from the spinning head. Bead formation began after about 15seconds and the product formation was completed in about 15-20 secondsactual spinning time.

The bead size production was as follows: 0.10% retained on No. 10 mesh;0.62% on No. 20 mesh; 21.10% on No. 40 mesh; 40.35% on No. 60 mesh;23.10% on No. 80 mesh; and 14.70% passed through No. 80 mesh. Thus, itcan be seen that a high degree of predictability of shearlites wereproduced from ascorbic acid using the process of the present invention.

Example VI Ascorbic Acid Tablet Production Without A Binder

The ascorbic acids shearlite particles produced in accordance withExample V were classified according sieve size. The portion passingthrough the No. 80 mesh was used to feed a tabletting press. Thetabletting press used was a Specac Model 15.011 tablet press.

Quite interestingly, the ascorbic acid product was able to be fedefficiently into the tablet press using a very small angle of repose. Byangle of repose, it is meant the angle required to induce flow of thetablet feedstock into the tablet press. A low angle of repose is highlydesirable for purpose of efficient processing.

Tablets were produced under 42 tons per square inch of pressure. Theresulting tablets displayed excellent cohesiveness and have a shinysurface which exhibited no sticking during removal from the die.Moreover, the superior tablet product prepared as a result of thepresent invention did not require a binder or any other additive toensure cohesiveness of the tablet.

Example VII Pseudoephedrine Beads

Two experiments were run to determine the processability ofpseudoephedrine as a feedstock material. The apparatus used in theseexamples is that depicted and described in FIGS. 4A, 4B, and 4C.

A feedstock consisting of 95% pseudoephedrine (Kroll 331151) and 5%polyethylene glycol (PEG 1450) was prepared by melting the polyethyleneglycol and adding thereto the pseudoephedrine and blending and thenpermitting the mixtures to solidify. The solidified mixture was thenpowdered in a grinding apparatus.

The spinning head was spun at 3300 rpm and the feedstock material wasintroduced until the material was reduced to liquiflash condition. Theproduct resulting therefrom was very uniform in shape and the majorityof the spheres were around 160 microns.

The results of this first experiment are shown in the photomicrograph ofFIG. 12A, and the dissolution characteristics have been depicted in 12C.As can be seen from these figures, the product was a very uniformspherical bead which demonstrated immediate dissolution of the activeingredient. The actual content of pseudoephedrine in the product shownin FIG. 12A and 12B was 95%.

A second portion of this example was performed using the sameingredients as reported in the first experiment and the outcome was alsosimilar.

The product, which has been shown here in FIG. 12B has a very uniformspherical shape having a size of between 160 and 180 μm. The actualcontent of active ingredient was 96.06%. The dissolution characteristicsare shown in FIG. 12D which depicts an excellent and predictable releaserate of the active ingredient.

Example VIII Pseudoephedrine And Glycerol Monostearate

In this example, 30% pseudoephedrine and 70% glycerol monostearate(Myverol 18-06) was blended and introduced to the apparatus shown inFIG. 4A, 4B, and 4C. The head was spun at 3300 rpm and the temperatureraised until the feedstock became liquiform.

The product formed as a result of the liquiflash processing was auniform spherical product ideally suited for inclusion in a deliverysystem. The product is shown in FIG. 13, which is a photomicrographtaken at 50×magnification.

Example IX Dextromethorphan and Glycerol Monostearate

In this example, the active, dextromethorphan, was mixed with glycerolmonostearate (Myverol 18-06). Dextromethorphan HBr (30%) was mixed with70% Myverol 18-06 brand glycerol monostearate blended and thenintroduced to a spinning head as described above.

The spinning head was run at 3300 rpm and the temperature raised untilthe feedstock was processed as a liquiform. Spheres appeared as twomajor size groups, one at the 40 to 80 micron range and another group atthe 160-200 micron range. These two groups were very uniform in shapeand many spheres showed small crystalline particles encapsulated withinthem. The product was very clean and have been shown in thephotomicrograph at 50×magnification in FIG. 14.

Example X Dextromethorphan-Pseudoephedrine Amalgam

In this example, a cough and cold treatment was produced by preparing anamalgam from pseudoephedrine and dextromethorphan. Shearlite particleswere made from the two active ingredients. Dextromethorphan HBr andpseudoephedrine HCI were mixed with Myverol 18-06 in amounts whichprovided 12.5% dextromethorphan, 25% pseudoephedrine, and 62.5% Myverol.The active agents were mixed and then added to Myverol after which theywere blended. The blend was then subjected to liquiflash processing at3300 rpm in an apparatus shown in FIGS. 4A-C.

The product was a shearlite particle very uniform in shape and size. Twosize groups were produced, one between 20 and 80 microns and anotherbetween 120 and 220 microns. A photomicrograph of the product is shownin FIG. 15.

The product was an excellent amalgam which can be used as a cough andcold medicinal treatment.

Example XI Chloropheniramine-Diphenhydramine-Pseudoephredine Amalgam

In this example, the active ingredients were combined to provide anothercough and cold treatment medicament. In particular, chloropheniraminemaleate was combined at a rate of 2.8% with 17.5% diphenhydramine HCIand 21% pseudoephredine HCI in combination with 58.7% Myverol 18-06. Theactive ingredients were blended and then mixed with Myverol and againblended.

The resulting mixture was liquiflash processed in an apparatus such asthat shown in FIGS. 4A-C at 3300 rpm. Photomicrographs of the productsproduced in accordance with this example are shown in FIG. 16.

Excellent shearlite particles were produced with the combination of thethree drugs. Two major size ranges were produced, one at 40-80 micronsand another at 160-220 microns.

This example shows that true amalgams can be formed of different activeingredients to provide medicinal treatments to suit the medicalpractitioner. Furthermore, coatings can be provided as desired inaccordance with the present invention. Thus, controlled-release andtaste masking can be effected by coating the shearlite particles.

Example XII Taste Comparison of Coated Unprocessed Ibuprofen and CoatedProcessed Ibuprofen

Raw ibuprofen feedstock was coated with Ethocel™ brandethylcellulose:PVP blend at 90:10 ratio. The coating were deposited at arate of 10% coating. Furthermore, ibuprofen shearlite particles preparedas set forth in Example IV were also coated at a rate of 10% coatingwith Ethocel™ brand coating.

Products resulting from both coating procedures were then subjected to ataste panel to determine whether or not effective taste masking had beenaccomplished. In a comparison between the two products, it was foundthat the raw ibuprofen was not effectively taste masked, while theprocessed ibuprofen had a high degree of taste masking.

Moreover, upon microscopic inspection, it was seen that the coating onunprocessed ibuprofen was uneven, whereas the processed ibuprofen wasevenly coated with a thin coating of the Ethocel™ brand coating.

Therefore, it can be seen that active agents converted to shearliteparticles by being subjected to liquiflash conditions provide aexcellent substrate for applying coating which masks the unappealingtaste of the active agent.

Example XIII Demonstration of Enhanced Flowability

Experiments were also conducted to demonstrate the enhanced flowabilityresulting from subjecting a feedstock material to liquiflash processing.

In one method, a flow rate test was conducted by using a funnel having aset diameter of 20 millimeters at the outlet thereof. A measured weightof raw feedstock, i.e, 30 grams, was poured into the funnel whileblocking the outlet side. The flow was then timed upon unblocking theoutlet. The active ingredients used in the test were acetaminophin andibuprofen.

Shearlite particles of both ingredients were prepared using theapparatus shown in FIGS. 4A-C. The ibuprofen was processed using 80%ibuprofen, 15% Compritol 888 ATO and 5% Gelucire. Acetaminophin wasprocessed without the addition of other ingredients.

The unprocessed ibuprofen and acetaminophin did not flow from the exitopening of the funnel even after administering tapping on the side ofthe funnel.

Both the ibuprofen and the acetaminophine which had been processed underliquiflash conditions, however, exit the opening of the funnel. Theibuprofen formula required one tap on the top of the funnel and theentire 30 grams emptied in only one second. The processed acetaminophinrequired no tapping on the funnel and passed through the exit opening ofthe funnel in less than one second.

Thus, the present invention can be seen to be highly effective inimproving the flow characteristic of active ingredients.

Example XIV Further Demonstration of Improved Flow Characteristic

In this example raw active agent and shearlite particles were tested tocompare improvement of the angle of repose. Thus, the ability of the rawmaterial to flow was directly compared to the flowability of theshearlite particle resulting from the present invention.

The method used to measure the angle of repose is a fixed cone method.Reference: "Multi-Particle Oral Drug Delivery," Isaac Ghebre-Sellassie,Vol. 65, Marcel Dekker, Inc., New York. In this method, powder isdropped through a funnel at a controlled distance from a dish which hasvertical sides. The powder is poured until it just touches the tip ofthe funnel. The radius of the powder circle in the dish and the heightto the tip of the funnel are measured. The comparison test were run byclamping a funnel 14 millimeters above the bottom of the glass petridish. The angle of repose is then calculated using the followingequation Tan φ=h/r or φ=Arctan h/r.

The results of the test indicated that only the shearlite particles ofacetaminophine and ibuprofen flowed through the funnel and thereforepossess a measurable angle of repose. The angle of repose is also verylow, i.e., less than 45°.

The results of the flow test have been set forth herein- below in theangle of repose table.

    ______________________________________                                        Material       Flow Rate   Angle of Repose                                    ______________________________________                                        Processed APAP less then 1 second                                                                        19.53°                                      100% Non-Processed                                                                           No Flow     NA                                                 APAP                                                                          Processed Ibuprofen                                                                          1 second    22.93°                                      Unprocessed Ibuprofen                                                                        No Flow     NA                                                 100% Ibuprofen Drug                                                                          No Flow     NA                                                 Unprocessed                                                                   ______________________________________                                    

It can be seen that the process of the present invention provides anactive ingredient with significantly enhanced flow characteristic.Basically, it converts non-flowable material to flowable material andimproves flowability where there is little or no flow capability.

Example XV Sucrose/Mannitol Spheres

Following the procedure of Example I, a 50--50 weight percent (wt. %)mixture of granulated sucrose and mannitol were subjected to liquiflashconditions utilizing a spinning head at 3600 rpm at approximately 195°C. The resulting product was 100% distribution of solid spheres. Thesesolid spheres, as in Example I, ranged in size from about 100 to about200 μm in diameter. These spheres are substantially solid throughout,and can be used in the variety of ways, such as an excipient in theproduction of dosage units. More importantly, the use of a 50--50 wt. %mixture of sucrose and mannitol facilitated 100% distribution ofspheres. Thus, the utilization of a 50--50 wt. % mixture of sucrose andmannitol facilitated a more efficient production of the shearliteparticles of the present invention.

Example XVI Direct Tableting Example

Acetaminophen shearlite particles, i.e., microspheres, prepared inaccordance with Example II were used to determine whether or not directtableting of acetaminophen microspheres could be accomplished. Thepresent example set forth the results of an attempt to deliver theacetaminophen microspheres directly to a tableting machine andcompressing under pressures of from 0.5 to 5 tons of force. In order toprepare the microspheres for tableting, 500 grams of 100% acetaminophenmicrospheres were passed through a 40 mesh screen and combined withapproximately 26.5 grams of sodium starch glycolate sold under thetrademark EXPLOTAB® by Edward Mendell Co.

The microsphere material was fed directly to a single press twelve (12)millimeter die and punch tableting apparatus. Compaction forces of from0.5 tons to 5 tons were used, i.e., 0.5 ton, 1 ton, 2 tons, 3 tons, 4tons and 5 tons of pressure.

The tablets made in accordance with the present example displayed nocapping or cracking and were rated as "non-sticky" to the tabletingapparatus. Moreover, the tablet mixture was free flowing and easilydirected to the twelve (12) millimeter die.

Each of the tablets were then immersed in an aqueous environment andpermitted to dissolve. As expected, tablets compressed at 0.5 tonsdissolved somewhat faster, while the tablets prepared under increasinglygreater compaction pressure disintegrated more slowly.

It is also important to note that in the present example, themicrospheres used for tableting readily flowed into the die cavity andare considered suitable for feeding into automated tableting machines.Thus, the experiment reported herein in Example XV demonstrates theability to subject microspheres to direct tableting without requirementof additional interim steps usually required to effect tableting intableting machines.

SHEARLITE EXCIPIENT EXAMPLES

In accordance with the present invention various active-containingtableting formulations were prepared using excipient shearlite particlesand active-containing shearlite particles. A summary of the range ofingredients to be used is shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Ingredients     Range      Preferred Range                                    ______________________________________                                        Excipient       0-99 wt. % 49.25-85 wt. %                                     Shearlite Particles                                                           Active-Containing                                                                              1-100 wt. %                                                                               15-50 wt. %                                      Shearlite Particles                                                           Flavoring Agents                                                                              0-20 wt. %  0.5-15 wt. %                                      (Including Sweeteners)                                                        Other Ingredients                                                                             0-15 wt. % 0.25-6 wt. %                                       (E.g., Humectants, Flow                                                       Agents, Binding Agents,                                                       Etc)                                                                          ______________________________________                                    

Example XVII Ibuprofen Tablets Utilizing Amorphous Sucrose Spheres

Ibuprofen tablets were prepared utilizing the amorphous sucrose spheres(shearlite particles) prepared in accordance with Example I, andIbuprofen shearlite particles. The Ibuprofen shearlite particles wereformed from a composition containing 88 wt. % ibuprofen, 10 wt. %Compritol 888, 2 wt. % Gelucire 50/13 core with a 12 wt. % coating ofEudragit® NE 30D, HPMCP, microtalc, and adipic acid, to produce acomposition having 77.4 wt. % total active ingredient.

The tableting formulation was prepared in the following manner. First,approximately 34.44 wt. % of ibuprofen shearlite particles was measured,to which 2.0 wt. % glycerin (a binding agent) was added thereto. Thismixture was agitated by hand for approximately 30 seconds. The mixturewas then placed in a turbulent mixer and agitated for approximatelythree minutes. Thereafter, 61.56 wt. % sucrose shearlite particles wasmeasured and added to the ibuprofen particles in 1/3 increments. Themixture was agitated in the turbulent mixer after each addition. Afterthe addition of the last increment, 0.5 wt. % lemon flavoring agent, 0.5wt. % whipped cream flavoring agent, 0.5 wt. % aspartame and 0.5 wt. %citric acid were added to form a 100 wt. % mixture. The resultingmixture was then reagitated for approximately two minutes in the mixer.

The tableting formulation was then fed directly into a single press 18millimeter die and punch tableting apparatus. Tablets were formedutilizing 60 pounds per square inch (psi) at a 0.2 second compressionduration. The resulting product of the compression were tablets thatwere too thin. This procedure was then repeated utilizing a 15millimeter die and punch tableting apparatus. The resulting tabletsexhibited satisfactory cohesion.

To ascertain if tablet hardness could be improved by an increase incompression force, the above procedure was repeated utilizing increasedcompression forces. A first run was conducted utilizing a compressionforce of 80 psi with a 15 millimeter die and punch tableting apparatusfor a compression duration of 0.2 seconds. The resulting tabletsexhibited an improved hardness in comparison to the tablets producedwith a compression force of 60 psi. The compression duration wassubsequently increased to 0.6 seconds to ascertain if an improvement inhardness could be achieved. The increased duration of compression didnot effect the tablet hardness. The compression force was increased to100 psi with a compression duration of 0.2 seconds. As a result of thisincreased compression force, a greater effort was required to remove thetablets from the tableting apparatus. Thus, a compression force of 80psi at a compression duration of 0.2 seconds provided the best resultsin tablet formation.

Example XVIII

In an attempt to improve extraction of the tablets from the tabletingapparatus, various concentrations of a flow agent, magnesium stearate,were added to the tableting formulation of Example XVII. In a first run,0.5 wt. % of magnesium stearate was added to a sample of the tabletingformulation of Example VIII. The tableting formulation was fed to a 15millimeter die and punch apparatus operating at 100 psi. A compressionduration of 0.2 seconds was utilized to form the tablets. This procedurewas then repeated utilizing a sample of tableting formulation fromExamples XVII with 1.0 wt. % of magnesium stearate. An improvementtablet extraction from the tableting apparatus was exhibited with bothformulations.

Example XIX

An ibuprofen tableting formulation in accordance with the tabletingformulation of Example XVII was prepared with a decreased concentrationof glycerin (i.e., binding agent). The tableting formulation contained62.56 wt. % amorphous sucrose spheres, 34.44 wt. % ibuprofen, 1.0 wt. %glycerin, 0.5 wt. % lemon flavoring agent, 0.5 wt. % whipped creamflavoring agent, 0.5 wt. % Aspartame and 0.5 wt. % citric acid, to givea 100 wt. % formulation. The formulation was free flowing and was easilydirected to the 15 millimeter die and punch. A compression force of 100psi for a compression duration 0.2 seconds was utilized. As in ExampleXVII, the greater compression force required an increased effort toextract the tablets from the tableting apparatus. Otherwise, theresulting tablets were satisfactory.

Example XX

An ibuprofen tableting formulation in accordance with of Example XIX wasprepared having a further decreased glycerin concentration. Theformulation contained 63.06 wt. % amorphous sucrose spheres, 34.44 wt. %ibuprofen, 0.5 wt. % glycerin, 0.5 wt. % lemon flavoring agent, 0.5 wt.% whipped cream flavoring agent, 0.5 wt. % aspartame, and 0.5 wt. %citric acid. Tablets were formed utilizing the procedure described inExample XIX. As in Example XIX, the resulting tablets required anincreased effort to extract the tablets from the tableting apparatus.Otherwise, the resulting tablets were satisfactory.

Example XXI

In an attempt to improve extraction of the tablets from the tabletingapparatus 0.5 wt. % magnesium stearate as a flow agent was added to asample of the ibuprofen composition of Example XIX. The formulationexhibited excellent flow properties and was easily directed to the 15millimeter die. A compression force of 100 psi was utilized for acompression duration of 0.2 seconds. The formed tablets exhibitedsatisfactory cohesion and were easily extracted from the tabletingapparatus.

Example XXII

An ibuprofen tableting formulation was prepared with a sample of thecomposition of Example XIX with 1.0 wt. % magnesium stearate as a flowagent. The formulation was tableted singularly on a half inch FFBEpunch. Although the tablets exhibited a high friability, they wereeasily extracted from the tableting apparatus.

Example XXIII

An ibuprofen tableting formulation was prepared utilizing a heat spunfloss as a supplement to the sucrose shearlite particle excipient of thepresent invention in order to ascertain the effects on tabletproduction. The formulation contained 30.8 wt. % floss having 3 wt. %lactose and 12 wt. % sorbitol therein, 30.8 wt. % the amorphous sucrosespheres, 34.4 wt. % ibuprofen, 2.0 wt. % glycerin, 0.5 wt. % lemonflavoring agent, 0.5 wt. % whipped cream flavoring agent, 0.5 wt. %aspartame and 0.5 wt. % citric acid. The formulation was tabletedutilizing a 15 millimeter die and punch at a compression force of 100psi for a compression duration of 0.2 seconds. The tableting formulationexhibited poor flow qualities and clumped together. The formed tabletsalso exhibited a patchy character, which was unsatisfactory.

Example XXIV

An ibuprofen tableting formulation was prepared having 50.0 wt. %amorphous sucrose spheres, 34.4 wt. % ibuprofen, 12.6 wt. % xylitab, 1.0wt. % glycerin, 0.5 wt. % lemon flavoring agent, 0.5 wt. % whipped creamflavoring agent, 0.5 wt. % aspartame and 0.5 wt. % citric acid. Theformulation was tableted utilizing a 15 millimeter die and punch at acompression force of 100 psi for a compression duration of 0.2 seconds.However, in this example, compression was repeated twice, i.e., two hitsper tablet, instead of once as in the previous examples. The resultingtablets exhibited a high friability and crumbled, and were, therefore,unsatisfactory.

Example XXV

An ibuprofen tableting formulation having pure sucrose floss as asupplement to the sucrose shearlite particle excipient was prepared. Thecomposition contained 50.0 wt. % amorphous sucrose spheres, 34.4 wt. %ibuprofen, 12.6 wt. % sucrose floss, 1.0 wt. % glycerin, 0.5 wt. % lemonflavoring agent, 0.5 wt. % whipped cream flavoring agent, 0.5 wt. %aspartame and 0.5 wt. % citric acid. The composition was tableted usinga 15 millimeter die and punch at a compression force of 100 psi for acompression duration of 0.2 seconds. As in Example XXIV, twocompressions were utilized in tablet formation. The resulting tabletsexhibited a grainy and porous surface appearance, which wasunsatisfactory.

Example XXVI

An ibuprofen tableting formulation as described in Example XXV wasproduced with the addition of 0.5 wt. % magnesium stearate as a flowagent. The composition was tableted using a 15 millimeter die and punchwith a compression force of 100 psi for a compression duration of 0.2seconds. Compression was repeated twice as in Examples XXIV and XXV. Theresulting tablets exhibited a grainy surface and crumbled. Thus, thetablets were considered unsatisfactory.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will appreciate that other and further modifications can be madewithout departing from the true spirit of the invention, and it isintended to include all other such modifications and changes as comewithin the scope of the invention as set forth in the appended claims.

What is claimed:
 1. A process for making a dosage unit, whichcomprises:directly tableting shearlite particles without intermediateprocessing or additional ingredients sufficiently to form a dosage unit,wherein said shearlite particles are provided by the process includingthe steps of: a) subjecting a solid, organic-based feedstock, capable ofbeing transformed to a liquiform in the substantial absence ofdissolving medium, to liquiflash conditions which transforms saidfeedstock from a solid to a liquid to a solid under conditions of heatand centrifugal force to provide substantially unimpeded internal flowof said feedstock while liquefied and said liquefied feedstock having aviscosity such that all impedance to form liquid droplets is eliminated;said transformation occurring in not greater than five (5) seconds; andb) imparting shear force on said flowing feedstock in step "a" in anamount sufficient to separate particles by natural mass separation ofsaid flowing feedstock in the presence of said shear force impingingthereon while in said unimpeded-flow condition.
 2. The process of claim1 wherein said discrete particles are microspheres.
 3. The process ofclaim 1 wherein said liquiflash conditions are provided by spinning saidfeedstock in a spinning head having a heated peripheral barrier withexit openings for passage of flowing feedstock therethrough in thepresence of centrifugal force provided by spinning said head.
 4. Theprocess of claim 1 wherein said shear force is imparted to said flowingfeedstock by the resistance of ambient atmosphere against said flowingfeedstock as it exits said spinning head.
 5. The process of claim 1which further comprises cooling said separated particles.
 6. The processof claim 1 wherein said discrete particles are monodispersed such thatat least about 40% by weight of the particles have a largest particlediameter within 60% of the mean particle diameter.
 7. The process ofclaim 1 wherein said feedstock comprises a medicament, an excipient andmixtures thereof.
 8. The process of claim 7 wherein said medicament isselected from the group of active agents consisting of antitussives,antihistamines, decongestants, alkaloids, mineral supplements,laxatives, vitamins, antacids, ion exchange resins,anti-cholesterolemics, anti-lipid agents, antiarrhythmics, antipyretics,analgesics, appetite suppressants, expectorants, anti-anxiety agents,anti-ulcer agents, anti-inflammatory substances, coronary dilators,cerebral dilators, peripheral vasodilators, anti-infectives,psycho-tropics, antimanics, stimulants, gastrointestinal agents,sedatives, antidiarrheal preparations, anti-anginal drugs,vasodialators, anti-hypertensive drugs, vasoconstrictors, migrainetreatments, antibiotics, tranquilizers, anti-psychotics, antitumordrugs, anticoagulants, antithromobotic drugs, hypnotics, anti-emetics,anti-nauseants, anti-convulsants, neuromuscular drugs, hyper- andhypoglycemic agents, thyroid and antithyroid preparations, diuretics,antispasmodics, uterine relaxants, mineral and nutritional additives,antiobesity drugs, anabolic drugs, erythropoietic drugs, antiasthmatics,cough suppressants, mucolytics, H₂ -antagonists, anti-uricemia drugs andmixtures thereof.
 9. The process of claim 1 wherein said directlytableting comprises transport of shearlite particles from a shearliteforming process to a tableting process.
 10. The process of claim 1wherein said shearlite particles comprise shearlite particles of amedicament and shearlite particles of an excipient.
 11. The process ofclaim 10 wherein said excipient shearlite particles are formed from afeedstock of a saceharide based material.
 12. A process for making adosage unit which comprises:tableting shearlite particles sufficientlyto form a dosage unit, wherein said shearlite particles are provided bya process which includes the steps of: a) subjecting a solid,organic-based feedstock, capable of being transformed to a liquiform inthe substantial absence of dissolving medium to liquiflash conditionswhich transforms said feedstock from a solid to a liquid to a solidunder conditions of heat and centrifugal force to provide substantiallyunimpeded internal flow of said feedstock while liquefied and saidliquefied feedstock having a viscosity such that all impedance to formliquid droplets is eliminated; said transformation occurring in notgreater than five (5) seconds; b) imparting shear force on said flowingfeedstock in step "a" in an amount sufficient to separate particles bynatural mass separation of said flowing feedstock in the presence ofsaid shear force impinging thereon while in said unimpeded flowcondition; and c) coating or adding at least one excipient to theparticles resulting from step "b".